text
stringlengths 34
10.9k
| page_idx
int64 9
2.25k
| document_name
stringclasses 1
value | file_path
stringclasses 1
value | file_url
stringclasses 1
value | loader_name
stringclasses 1
value |
|---|---|---|---|---|---|
ix
PREFACE
As a general rule, the orientation of diagrams and photographs
throughout the book has been standardized to show the left side of the
body, irrespective of whether a lateral or medial view is presented, and
transverse sections are viewed from below to facilitate comparison with
clinical images. Clinicopathological examples have been selected where
the pathology is either a direct result, or a consequence, of the anatomy,
or where the anatomical features are instrumental in the diagnosis/
treatment/management of the condition. Wherever possible, the photo
micrographs illustrate human histology and embryology; non human
sources are acknowledged in the captions.
In an ideal world, anatomical terminology would satisfy both anat
omists and clinicians. For the avoidance of doubt, the same word should be agreed and used for each structure that is described, whether
in the anatomy laboratory or the clinic. In the real world, this goal is
achieved with varying degrees of success; alternative terms (co)exist and
may (and frequently do) confuse or frustrate. Currently, Terminologia
Anatomica (TA)
1 is the reference source for the terminology for macro
scopic anatomy; the text of the forty first edition of Gray’s Anatomy is
almost entirely TA compliant. However, where terminology is at vari
ance with, or, more likely, is not included in, the TA, the alternative term that is chosen either is cited in the relevant consensus document
or position paper – e.g. ‘European Position Paper on the Anatomical
Terminology of the Internal Nose and Paranasal Sinuses’
2 and the Inter
national Interdisciplinary Consensus Statement on the ‘Nomenclature of the Veins of the Lower Limbs’
3 – or enjoys widespread clinical usage:
for example, the use of attitudinally appropriate terms in cardiology (see Chapter 57). The continued use of eponyms is contentious.
4 Pro
ponents of their retention argue that some eponyms are entrenched in medical language and are (therefore) indispensable, that they facilitate
communication because their use is so pervasive and that they serve to
remind us of the humanism of medicine. Detractors argue that eponyms
are inherently inaccurate, non scientific and often undeserved. In this
edition of Gray’s Anatomy, synonyms and eponyms are given in paren
theses on first usage of a preferred term and not shown thereafter in the
text; an updated list of eponyms remains available in the e book for
reference purposes.
I offer my sincere thanks to the editorial team at Elsevier, initially
under the leadership of Madelene Hyde and latterly of Jeremy Bowes,
for their guidance, professionalism, good humour and unfailing
support. In particular, I thank Poppy Garraway, Humayra Rahman
Khan, Wendy Lee, Joanna Souch, Julie Taylor, Jan Ross and Louise Cook,
for being at the end of a phone or available by e mail whenever I needed
advice or support.
I dedicate my work on the forty first edition of Gray’s Anatomy to the
memory of my late husband, Guy Standring.
Susan Standring
January 2015‘Anatomy is the basis of medical discourse. ’
(Hippocrates, De locis in homine 2)
Looking through an almost complete set of the previous editions of Gray’s Anatomy, I am struck by the marked difference in size between
the first and fortieth editions. That progressive increase in girth has
occurred pari passu
with ground breaking advances in basic science and
clinical medicine over the past 155 years. Anatomy has become a far wider discipline than Henry Gray, Henry van Dyke Carter or any of their
students could have envisaged. Fields such as cell biology, molecular
genetics, neuroanatomy, embryology and bioinformatics either had not
emerged or were in their infancy in 1858. Techniques that today inform
our view of the internal landscape of the body – such as specialized
types of light and electron microscopy; imaging modalities, including
Xrays, magnetic resonance imaging, computed tomography and ultra
sonography; the use of ‘soft’ perfusion techniques and frozen thawed,
unembalmed cadavers for dissection based studies; and the advances
in information technology that enable endoscopic and robotic surgery
and facilitate minimally invasive access to structures previously consid
ered inaccessible – were all unknown. As each development entered mainstream scientific or clinical use, the new perspectives on the body
it afforded, whether at submicroscopic or macroscopic level, filtered
into the pages of Gray’s Anatomy
: for example, the introduction of X ray
plates (twenty seventh edition, 1938) and electron micrographs (thirty
second edition, 1958).
In the Preface to the first edition, Henry Gray wrote that ‘ This Work
is intended to furnish the Student and Practitioner with an accurate view of the Anatomy of the Human Body, and more especially the application of this
science to Practical Surgery. ’ We remain true to his intention. An appropri
ate knowledge of clinically relevant, evidence based anatomy is an
essential element in the armamentarium of a practising clinician;
indeed, ‘If anything, the relevance of anatomy in surgery is more impor
tant now than at any other time in the past’ (Tubbs, in Preface Com
mentary, which accompanies this volume).
In my Preface to the fortieth edition, I intimated that the book was
quite literally in danger of breaking its binding if any more pages were
added. In order to avoid this unfortunate occurrence, the forty first
edition contains a significant amount of material that is exclusively electronic, in the form of 77,000 words of additional text, 300 artworks
and tables, 28 videos and 24 specially invited commentaries on topics
as diverse as electron microscopy and fluorescence microscopy; the
neurovascular bundles of the prostate; stem cells in regenerative medi
cine; the anatomy of facial ageing; and technical aspects and applica
tions of diagnostic radiology. In keeping with the expectation that
anatomy should be evidence based, the forty first edition contains
many more references in the e book than could be included in the
thirty ninth and fortieth printed editions.
Neel Anand, Rolfe Birch, Pat Collins, Alan Crossman, Michael
Gleeson, Ariana Smith, Jonathan Spratt, Mark Stringer, Shane Tubbs, Alan Wein and Caroline Wigley brought a wealth of scholarship and
experience as anatomists, cell biologists and clinicians to their roles as
Section Editors. I thank them for their dedication and enthusiastic
support, in selecting and interacting with the authors in their Sections
and for meeting deadlines, despite the ever increasing demands on
their time from university and/or hospital managers. Pat Collins, Girish Jawaheer, Richard Tunstall and Caroline Wigley worked closely
with many authors to update the text and artworks for organogenesis,
paediatric anatomy, evidence based surface anatomy and microstruc
ture, respectively, across Sections 3 to 9. Jonathan Spratt acted as both
a Section Editor (thorax) and an indefatigable ‘go to’ for sourcing images throughout the book; in the latter capacity, he has produced
a superb collection of additional labelled images, available in the
ebook (see Bonus imaging collection). Over a hundred highly experi
enced anatomists and clinicians contributed text, often extensively revised from the previous edition, and/or artworks, original micro
graphs or other images to individual chapters.
1Terminologia Anatomica (1998) is the joint creation of the Federative Committee on
Anatomical Terminology (FCAT) and the Member Associations of the Interna
tional Federation of Associations of Anatomists (IFAA).
2Lund VJ, Stammberger H, Fokkens WJ et al 2014 European position paper on the
anatomical terminology of the internal nose and paranasal sinuses. Rhinol Suppl
24:1–34.
3Caggiati A, Bergan JJ, Gloviczki P et al; International Interdisciplinary Consensus
Committee on Venous Anatomical Terminology 2005 Nomenclature of the veins of the lower limb: extensions, refinements, and clinical application. J Vasc Surg 41:719–24.
4Amarnani A, Brodell RT , Mostow EN 2013 Finding the evidence with eponyms . JAMA
Dermatol 149:664–5; Fargen KM, Hoh BL 2014 The debate over eponyms. Clin Anat 27:1 137–40; Lo WB, Ellis H 2010 The circle before Willis: a historical account of the intracranial anastomosis . Neurosurgery 66:7–18; Ma L, Chung KC 2012 In
defense of eponyms . Plast Reconstr Surg 129 :896e–8e. | 9 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
e1
The continuing relevance of anatomy in
current surgical practice and researchPREFACE
COMMENTARY
When our anatomy forebears embarked on the uncharted study of the
human body, they did so without reference. Their focus was to chart
and map the body simply to learn and describe intricacies never chroni -
cled before. The anatomical ‘map’ we use today came about thanks to figures such as da Vinci, Vesalius, Cheselden and, more recently, Henry
Gray. On the shoulders of these giants, we see farther than our predeces-
sors. In The Metalogicon, published in 1 159, John Salisbury recognized
the profound observation of French philosopher Bernard of Chartres, who declared that ‘ ...we are like dwarfs on the shoulders of giants, so that
we can see more than they, and things at a greater distance, not by virtue of any sharpness of sight on our part, or any physical distinction, but because
we are carried high and raised up by their giant size’ . So, with the gross
anatomy of man presumed, by many scholars, to have been described and understood long ago, how does the modern anatomist bring rel -
evance to the continued study of morphology? Is there any uncharted territory for the modern anatomist to plot in order to sustain our field
of study and for it to continue to be perceived as relevant to an educa-
tional world, and to medical and dental curricula in which the time
allotted to anatomical study has significantly waned? Simply put, yes.
Henry Gray, based on the title of his original text, Anatomy, Descriptive
and Surgical, knew very well that there was a need to refocus the lenses of teaching and research in the anatomical sciences, and to expand and
explore their surgical relevance. Our gross anatomical map of the
human body must continue to be updated and legends must continue
to be placed on that map to incorporate modern advances in technol -
ogy. New methods of surgery, such as laparoscopy and endoscopy, as well as the use of the surgical microscope, offer the opportunity to view
the human form in a different light and in greater surgical detail than
ever before. If anything, the relevance of anatomy in surgery is more
important now than at any other time in the past. The modern surgeon
must take what is learned macroscopically, in the dissection room, and
apply this knowledge to structures seen under magnification and
through instruments that provide a surgical field that is, at times, just
millimetres in diameter. Therefore, attention to anatomical detail is of
vital importance as references and anatomical landmarks are mini -
mized in the surgical theatre of the new millennium.
As mentioned before, early anatomists dissected with curiosity about
the unknown and gained knowledge that would become a prerequisite for proper surgical manœuvres. Today, as anatomists, our anatomical
knowledge should create in us a curiosity about what we can do with
the knowledge that we have gained. The ability to apply that knowledge
offers an opportunity to be an integral part of the ever-progressing field
of surgery. For example, today, surgical problems are often the impetus
for dissection studies, which can influence the way in which surgery is
performed and, moreover, can sway the way in which anatomy is taught
(e.g. redefining a focus in condensed curricula and with decreased work
hours for house officers). Surgically, dissection studies have allowed us
to manipulate known human anatomy and to solve, for example,
complex neurological problems. As an illustration of the surgical rele -
vance of modern-day anatomical studies for neurological pathologies, we have conducted, in my laboratory, cadaveric feasibility studies that
suggested that the phrenic nerve could be reinnervated in high quadri -
plegic patients who are ventilator-dependent (a morbid condition with an associated high mortality rate) by using the intact, adjacent accessory
nerve (i.e. neurotization) (Tubbs et al 2008a) ( Fig. 1.6.1). The theory
behind this investigation was that the functioning accessory nerve
would be used to form a new circuit between it and the dysfunctional
phrenic nerve, and that this would allow recovery of diaphragm func -
tion. For this technique, a longitudinal incision was made along the lower half of the posterior border of sternocleidomastoid. Dissection was then performed in order to identify both the accessory nerve at this level, at its entrance into trapezius, and the phrenic nerve crossing anterior to scalenus anterior. The medial half of the accessory nerve was then split away from its lateral half and transected at its entrance into muscle. This distally disconnected medial half of the nerve was then
swung medially to the phrenic nerve, which had been transected proxi -
mally. The two nerves were then sutured together without tension. This ‘rearranging’ of human anatomy has now been employed clinically with
success. Yang et al (201 1) used our study results to treat a 44-year-old
man with complete spinal cord injury at the C2 level. Clinically, left diaphragm activity was decreased and the right diaphragm was com -
pletely paralysed. Four weeks after surgery, training of the synchronous activities of trapezius and inspiration was conducted. Six months after
surgery, motion was observed in the previously paralysed right dia -
phragm. Evaluation of lung function indicated improvements in vital capacity and tidal volume. The patient was able to sit in a wheelchair
and conduct activities without assisted ventilation 12 months after
surgery. For the surgeon, such manipulation of anatomy requires a
comprehensive understanding not only of normal anatomy but also of
what might occur functionally by rewiring such nerves. For example,
patients undergoing this surgery will initially need to think of moving
their trapezius to activate their diaphragm. With time, this will not be
the case. Similar illustrations of the plasticity of the brain have been
seen in patients undergoing hypoglossal to facial nerve neurotization
procedures; these patients at first need to think of moving their tongue
in order for their facial muscles to contract.
Rewiring of nerves has been addressed in other studies. Thus, we
have shown, first in a cadaveric study (Hansasuta et al 2001) and then
clinically (Wellons et al 2009), that the medial pectoral nerve can be
sectioned near its entrance into the deep surface of pectoralis major and
swung round and sewn into the musculocutaneous nerve ( Fig. 1.6.2).
If this procedure is successful, axonal regrowth from the medial pectoral
nerve into the musculocutaneous nerve (about 1 mm/day) will
re-establish function in the anterior arm muscles; the loss of clinically significant function of the dually innervated pectoralis major is minimal
and the functional gain of having the anterior arm muscles work is
significant (Wellons et al 2009). Being able to bring the hand to the
mouth and feed oneself is a task that most take for granted. In children
with birth-related injuries to the upper brachial plexus (i.e. Erb’s palsy),
this movement is often the difference between waiting to be fed or
feeding oneself. This method has been used at our institution for over
15 years with an 80% success rate, where success is measured as the
patient regaining function of arm flexion.
Another example of what we have termed ‘reverse translational
research in anatomy’ (i.e. from the bed to the bench and back) is the location of new anatomical diversionary sites (in this case, the medul -
lary cavity of the ilium) that could be used in patients with cerebrospi -
nal fluid absorption problems (i.e. hydrocephalus) and in whom the
traditionally used receptacles for absorbing this diverted cerebrospinal
fluid (e.g. peritoneal and pleural cavities, heart) are not options, as a
consequence of e.g. malabsorption or local infection (Tubbs et al 2015)
(Fig. 1.6.3). This alternative site has, for the first time, just been used and with success (unpublished data). Although not proven clinically,
an earlier study in primates showed that the manubrium of the sternum
could also be used as a distal receptacle for cerebrospinal fluid collec -
tion (Tubbs et al 201 1). After tubing was tunnelled from the cannulated
ventricle, the distal tubing was inserted subcutaneously into the supe -
rior aspect of the midline manubrium, where a small hole had been
drilled. Up to 50 ml of saline per hour could be infused into the primate
sternum without vital sign changes. This study, and the study using the
ilium as a depository, both demonstrate the anatomical continuity
between the bony medullary cavities and the vascular system. Such positive effects on patient outcomes not only make the study of human anatomy from a slanted perspective extremely gratifying, but are also practical since the results have direct application in the surgical theatre.
In addition to surgical anatomy playing a role in new uses of the
normal anatomy, this field can also explore and direct new surgical approaches where the goals are to make surgery more effective and R Shane Tubbs | 10 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
The con Tinuing relevance of ana Tomy in curren T surgical prac Tice and research
e2treatment, resulted in a more limited laminectomy and myelotomy,
and, in one case, assisted in identifying a residual spinal cord tumour.
It was also useful in the fenestration of a multilevel spinal arachnoid
cyst and in confirming communication of fluid spaces in the setting of
a complex holocord syrinx. Endoscopy aided the visualization of the
spinal cord to ensure the absence of tethering in the case of split spinal
cord malformation. These endoscopic approaches were only possible
by knowing the normal anatomy and how it appears in a confined field
of view, as first seen in the anatomy laboratory.
Lastly, the anatomist can add to the relevance of anatomy for the
surgeon with studies that have an impact on the identification or avoid -
ance of important structures during operative manœuvres (i.e. anatomi -
cal landmark studies). My group has defined surgical landmarks for
anatomical structures such as the superior and inferior gluteal nerves
(Apaydin et al 2013, Apaydin et al 2009); vein of Labbé (Tubbs et al
2012); sigmoid sinus (Tubbs et al 2009a); amygdala (Tubbs et al minimally invasive, and involve fewer complications. For example, we
have performed feasibility studies looking at a wide range of novel
approaches that might be used by the surgeon. These include a dorsal
approach to the carpal tunnel for an entrapped median nerve (Tubbs
et al 2005a); an anterior approach to the sciatic nerve potentially com -
pressed by piriformis via the obturator foramen (Tubbs, unpublished
data); an anterior approach to the upper thoracic vertebrae for spine
fusion procedures (Tubbs et al 2010a); an intra-abdominal laparoscopic
approach to decompress the pudendal nerve (Loukas et al 2008); and
midline endoscopic approaches to the fourth ventricle with application
to decompressing a ‘trapped’ fourth ventricle, as is seen in some cases
of hydrocephalus (Tubbs et al 2004). We have also explored the feasibil -
ity in cadavers of using endoscopy for exploration of pathologies of the
thecal sac (Chern et al 201 1). In a series of children with intraspinal
pathology (arachnoid cyst, spinal cord tumour, holocord syrinx and split cord malformation), intradural spinal endoscopy was a useful Fig. 1.6.1 A schematic representation of the
anatomically defined technique of using the
accessory nerve for neurotization of the phrenic
nerve with application to patients with high
cervical quadriplegia who are ventilator-
dependent. With nerve regrowth, axons from the
intact and functioning accessory nerve travel into
the phrenic nerve to reinnervate this nerve and
restore diaphragmatic function. In this example,
only one-half of the accessory nerve is used in
order to maintain some function of trapezius.
(Drawn by Mr David Fisher.)
Fig. 1.6.2 The neurotization of the
musculocutaneous nerve with the medial pectoral nerve (inset). Similar to the example illustrated in
Figure 1.6.1, such a method of nerve repair is
employed in the hope that a patient with an upper
brachial plexus injury and anterior arm muscles
that are dysfunctional can regain function by
regrowth of axons from the intact medial pectoral
nerve into and along the musculocutaneous nerve.
(Drawn by Mr David Fisher.)
| 11 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
The continuing relevance of anatomy in current surgical practice and research
e3
(Loukas et al 2006); long thoracic nerve (Tubbs et al 2006b); anterior
interosseous nerve (Tubbs et al 2006c); accessory nerve (Tubbs et al
2005b); lumbar plexus and its branches (Tubbs et al 2005c); trochlear
nerve (Tubbs and Oakes 1998); and frontal sinus (Tubbs et al 2002).
Such studies might assist in decreasing the morbidity and increasing
the efficiency of surgical approaches and certainly illustrate the surgical
relevance of anatomy. Moreover, this list exemplifies the multitude of
anatomical structures that may be given greater surgical relevance by
addressing how they may be more accurately located in the operating
theatre.
In this day and age, if anatomists are not to lose their footing and
simply be considered teachers of an old and outdated discipline, the
onus is on us to renew interest in our field with timely and salient
studies that gird the loins of a profession that is in danger of becoming
extinct. It is my opinion, and that of others, that one effective way to
achieve this is to remind the world by demonstrations such as those
listed here that the study of anatomy is as clinically relevant today as it
was at its humble beginnings. Considering the adage that anatomy is
the oldest child of Mother Medicine, the fact that surgical problems and
anatomical studies go hand in hand is obvious – anatomical research
is not a ‘dead’ science! The modern relevance of anatomy to surgical
practice and research must not be underestimated.Fig. 1.6.3 The technique used in a patient with hydrocephalus to divert
cerebrospinal fluid from the cerebral ventricles to the ilium. The enlarged
ventricles are cannulated with a catheter connected to a subcutaneous
valve that drains into tubing tunnelled under the skin and then implanted
into the medullary cavity of the ilium; here, the cerebrospinal fluid is
absorbed into the vascular system. The techniques described in Figures
1.6.2 and 1.6.3, based on surgical problems and manipulation of known
anatomy for surgical benefit, were evaluated and studied in the anatomy
laboratory, and have now been used clinically. (Drawn by Mr David
Fisher.)
Fig. 1.6.4 A superior view of the cranium, with the underlying superior
sagittal sinus, cortical veins and lateral lacunae illustrated. This study explored the relationship between the underlying lateral lacunae and the
overlying coronal and sagittal sutures, and made measurements between
these structures. Neurosurgically, the initial placement of burr-holes
avoids the midline in order to prevent damage to the superior sagittal
sinus. However, the intracranial entrance of the drill often injures more
laterally placed lacunae. Using surface anatomy based on anatomical
landmarks, a neurosurgeon can be more aware of the locations of these
underlying structures while performing craniotomies. Such landmarks
have now been used by neurosurgeons at our institution. (Drawn by Mr
David Fisher.)
2010b); buccal branch of the trigeminal nerve (Tubbs et al 2010c);
radial nerve and posterior interosseous branch (Cox et al 2010, Tubbs
et al 2006a); perineal branch of the posterior femoral cutaneous nerve
(Tubbs et al 2009b); lateral lacunae (Tubbs et al 2008b) ( Fig. 1.6.4);
basal vein of Rosenthal (Tubbs et al 2007); greater occipital nerve
REFERENCES
Apaydin N, Bozkurt M, Loukas M et al 2009 The course of the inferior gluteal
nerve and surgical landmarks for its localization during posterior
approaches to hip. Surg Radiol Anat 31:415-18.Apaydin N, Kendir S, Loukas M et al 2013 Surgical anatomy of the superior
gluteal nerve and landmarks for its localization during minimally inva -
sive approaches to the hip. Clin Anat 26:614–20. | 12 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
The con Tinuing relevance of ana Tomy in curren T surgical prac Tice and research
e4Tubbs RS, Miller JH, Cohen-Gadol AA et al 2010b Intraoperative anatomic
landmarks for resection of the amygdala during medial temporal lobe
surgery. Neurosurgery 66:974–7.
Tubbs RS, Miller J, Loukas M et al 2009b Surgical and anatomical landmarks
for the perineal branch of the posterior femoral cutaneous nerve: impli -
cations in perineal pain syndromes. Laboratory investigation. J Neuro -
surg 1 1 1:332–5.
Tubbs RS, Oakes WJ 1998 Relationships of the cisternal segment of the
trochlear nerve. J Neurosurg 89:1015–19.
Tubbs RS, Pearson B, Loukas M 2008a Phrenic nerve neurotization utilizing
the spinal accessory nerve: technical note with potential application in
patients with high cervical quadriplegia. Childs Nerv Syst 24:1341–4.
Tubbs RS, Salter EG, Custis JW et al 2006b Surgical anatomy of the cervical
and infraclavicular parts of the long thoracic nerve. J Neurosurg 104:
792–5.
Tubbs RS, Salter EG, Sheetz J et al 2005a Novel surgical approach to the
carpal tunnel: cadaveric feasibility study. Clin Anat 18:350–6.
Tubbs RS, Salter EG, Wellons JC 3rd et al 2005b Superficial landmarks for
the spinal accessory nerve within the posterior cervical triangle. J Neu -
rosurg Spine 3:375–8.
Tubbs RS, Salter EG, Wellons JC 3rd et al 2005c Anatomical landmarks for
the lumbar plexus on the posterior abdominal wall. J Neurosurg Spine
2:335–8.
Tubbs RS, Salter EG, Wellons JC 3rd et al 2006a Superficial surgical land -
marks for identifying the posterior interosseous nerve. J Neurosurg
104:796–9.
Tubbs RS, Tubbs I, Loukas M et al 2015 Ventriculoiliac shunt: a cadaveric
feasibility study. J Neurosurg Pediatr 15:310–12.
Tubbs RS, Wellons JC 3rd, Salter G et al 2004 Fenestration of the superior
medullary velum as treatment for a trapped fourth ventricle: a feasibility
study. Clin Anat 17:82–7.
Wellons JC, Tubbs RS, Pugh JA et al 2009 Medial pectoral nerve to muscu-
locutaneous nerve neurotization for the treatment of persistent birth-
related brachial plexus palsy: an 1 1-year institutional experience.
J Neurosurg Pediatr 3:348–53.
Yang ML, Li JJ, Zhang SC 201 1 Functional restoration of the paralyzed dia -
phragm in high cervical quadriplegia via phrenic nerve neurotization
utilizing the functional spinal accessory nerve. J Neurosurg Spine 15:
190–4.Chern JJ, Gordon AS, Naftel RP et al 201 1 Intradural spinal endoscopy in
children. J Neurosurg Pediatr 8:107–1 1.
Cox CL, Riherd D, Tubbs RS et al 2010 Predicting radial nerve location using
palpable landmarks. Clin Anat 23:420–6.
Hansasuta A, Tubbs RS, Grabb PA 2001 Surgical relationship of the medial
pectoral nerve to the musculocutaneous nerve: a cadaveric study. Neuro -
surgery 48:203–6.
Loukas M, El-Sedfy A, Tubbs RS et al 2006 Identification of greater occipital
nerve landmarks for the treatment of occipital neuralgia. Folia Morphol
(Warsz) 65:337–42.
Loukas M, Louis RG Jr, Tubbs RS et al 2008 Intra-abdominal laparoscopic
pudendal canal decompression – a feasibility study. Surg Endosc 22:
1525–32.
Tubbs RS, Bauer D, Chambers MR 201 1 A novel method for cerebrospinal
fluid diversion: a cadaveric and animal study. Neurosurgery 68:491–4.
Tubbs RS, Custis JW, Salter EG et al 2006c Quantitation of and superficial
surgical landmarks for the anterior interosseous nerve. J Neurosurg
104:787–91.
Tubbs RS, Elton S, Salter G et al 2002 Superficial surgical landmarks for the
frontal sinus. J Neurosurg 96:320–2.
Tubbs RS, Johnson PC, Loukas M et al 2010c Anatomical landmarks for
localizing the buccal branch of the trigeminal nerve on the face. Surg
Radiol Anat 3:933–5.
Tubbs RS, Louis RG Jr, Song YB et al 2012 External landmarks for identifying
the drainage site of the vein of Labbé: application to neurosurgical
procedures. Br J Neurosurg 26:383–5.
Tubbs RS, Loukas M, Callahan JD et al 2010a A novel approach to the upper
anterior thoracic spine: a cadaveric feasibility study. J Neurosurg Spine 13:346–50.
Tubbs RS, Loukas M, Louis RG Jr et al 2007 Surgical anatomy and landmarks
for the basal vein of Rosenthal. J Neurosurg 106:900–2.
Tubbs RS, Loukas M, Shoja MM et al 2008b Lateral lakes of Trolard: anatomy,
quantitation, and surgical landmarks. Laboratory investigation. J Neu -
rosurg 108:1005–9.
Tubbs RS, Loukas M, Shoja MM et al 2009a Surface landmarks for the junc -
tion between the transverse and sigmoid sinuses: application of the ‘strategic’ burr hole for suboccipital craniotomy. Neurosurgery 65:
37–41. | 13 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
xACKNOWLEDGEMENTS
Within individual figure captions, we have acknowledged all figures kindly loaned from other sources. However, we
would particularly like to thank the following authors who have generously loaned so many figures from other books published by Elsevier:
Drake RL, Vogl AW, Mitchell A (eds), Gray’s Anatomy for Students, 2nd ed. Elsevier, Churchill Livingstone. Copyright
2010.
Drake RL, Vogl AW, Mitchell A, Tibbitts R, Richardson P (eds), Gray’s Atlas of Anatomy. Elsevier, Churchill
Livingstone. Copyright 2008.
Waschke J, Paulsen F (eds), Sobotta Atlas of Human Anatomy, 15th ed. Elsevier, Urban & Fischer. Copyright 2013.Acknowledgements for paediatric anatomy content in chapter 45 to Ritchie Marcus, MD and Guirish A. Solanki, MD,
Birmingham Children’s Hospital, UK, and for chapter 81 to Christopher Edward Bache, MBChB, FRCS (Tr & Orth),
Birmingham, UK. The editors would like to thank all contributors and illustrators to the previous editions of Gray’s
Anatomy, including the fortieth and thirty-ninth editions. Much of the illustration in Gray’s Anatomy has as its basis
the work of illustrators and photographers who contributed towards earlier editions, their figures sometimes being
retained almost unchanged, and sometimes being used as the foundation for figures that are new to this edition. | 14 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
xi
CONTRIBUTORS TO THE FORTY-FIRST EDITION
Graham J Burton MD, DSc, FMedSci
Mary Marshall and Arthur Walton Professor
of the Physiology of Reproduction
Centre for Trophoblast Research
University of Cambridge
Cambridge, UK
Andrew Bush MD, FRCP, FRCPCH, FERS
Professor of Paediatrics and Head of Section
(Paediatrics)
Imperial College;
Professor of Paediatric RespirologyNational Heart and Lung Institute;Consultant Paediatric Chest PhysicianRoyal Brompton and Harefield NHS
Foundation Trust
Paediatric Respiratory MedicineLondon, UK
Alison Campbell BSc(Hons), MMedSci,
DipRCPath
Group Director of Embryology
CARE Fertility
Nottingham, UK
Bodo EA Christ MD
Professor and Former Chairman
Department of Molecular Embryology
University of Freiburg
Freiburg, Germany
Thomas Collin MBBS, FRCS(Plast)
Consultant Plastic and Reconstructive Surgeon
University Hospital of North DurhamDepartment of Plastic Surgery
Durham, UK
Patricia Collins BSc, PhD, FHEA
Professor of Anatomy
Anglo-European College of ChiropracticBournemouth, UK;
Editor for Embryology and Development
Anthony T Corcoran MD
Assistant Professor of Urologic Oncology
and Minimally Invasive Surgery
Department of UrologySUNY Stony Brook School of Medicine
Stony Brook, NY, USA
Julie Cox FRCS(Eng), FRCR
Consultant Radiologist
City Hospitals Sunderland NHS
Foundation Trust Sunderland, UK
Alan R Crossman BSc, PhD, DSc
Professor Emeritus
University of ManchesterManchester, UKMichael A Adams BSc, PhD
Professor of BiomechanicsCentre for Comparative and Clinical AnatomyUniversity of Bristol, UK
L Max Almond MB, ChB, MRCS, MD
Senior Registrar in Gastrointestinal Surgery
West Midlands DeaneryBirmingham, UK
Neel Anand MD
Clinical Professor of Surgery
Director, Spine Trauma, Minimally Invasive
Spine Surgery
Spine CenterCedars Sinai Medical Center
Los Angeles, CA, USA
Nihal Apaydin MD, PhD
Associate Professor of Anatomy
Department of Anatomy and Brain Research
Center
Ankara University Faculty of MedicineAnkara, Turkey
Lily A Arya MD, MS
Associate Professor of Obstetrics and
Gynecology
Perelman School of Medicine
University of PennsylvaniaDepartment of Obstetrics and GynecologyPhiladelphia, PA, USA
Tipu Aziz FMedSci
Professor of Neurosurgery
John Radcliffe Hospital
University of OxfordOxford, UK
Jonathan BL Bard MA, PhD
Emeritus Professor of Development and
Bioinformatics
School of Biomedical Sciences
University of EdinburghEdinburgh, UK
Eli M Baron MD
Clinical Associate Professor of Neurosurgery
Spine Surgeon, Cedars SinaiDepartment of NeurosurgeryCedars Sinai Spine Center, Cedars Sinai
Medical Center
Los Angeles, CA, USA
Hugh Barr MD(Dist), ChM, FRCS(Eng),
FRCS(Ed), FHEA, FODI
Consultant General and Gastrointestinal
Surgeon
Oesophagogastric Resection Unit
Gloucestershire Royal Hospital
Gloucester, UKBrion Benninger MD, MSc
Professor, Executive DirectorMedical Anatomy Center – Innovation and
Technology Research
McDaniel Surgical, Radiological & Education
Research Lab
Departments of Medical Anatomical
Sciences & Neuromuscular Medicine
Western University of Health Sciences,
Lebanon, Oregon
Faculty Orthopaedics & Surgical Residency
Training
Faculty Sports Medicine Fellowship Training
Samaritan Health Services, Corvallis, Oregon
USA
Barry KB Berkovitz BDS, MSc, PhD, FDS,
LDSRCS(Eng)
Emeritus Reader in Dental AnatomyAnatomy Department
King’s College LondonLondon, UK;Visiting ProfessorOman Dental CollegeOman
Leela C Biant BSc(Hons), MBBS, AFRCSEd,
FRCSEd(Tr & Orth), MSres(Lond), MFSTEd
Consultant Trauma and Orthopaedic
Surgeon
Royal Infirmary of Edinburgh;
Honorary Senior Lecturer
University of EdinburghNRS Career Clinician Scientist FellowEdinburgh, UK
Rolfe Birch MChir, FRCPS(Glasg),
FRCS(Ed), FRCS(Eng)
Retired Consultant in Charge
War Nerve Injury Clinic, Defence Medical
Rehabilitation Centre, Surrey;
Retired Head, Peripheral Nerve Injury Unit,
Royal National Orthopaedic Hospital;
Professor in Neurological Orthopaedic
Surgery, University College of London
London, UK
Martin A Birchall MD, FRCS, FMedSci
Professor of Laryngology
Consultant Otolaryngologist, Ear Institute
University College London and Royal
National Throat Nose and Ear Hospital
University College Hospitals NHS Foundation
Trust
London, UK
Sue Black OBE, BSc, PhD, DSc, FRSE,
FRAI, FRCP, FSB
Professor of Anatomy and Forensic
Anthropology
Centre for Anatomy and Human Identification
University of DundeeScotland, UKThe editors would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition would not have been possible. | 15 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Contributors to the forty-first edition
xiiNatalie M Cummings BSc(Med Sci),
MB ChB, MPhil, MD, MRCP(Ed)
Consultant Respiratory Physician
University Hospital of North Durham
Durham, UK
Anthony V D’Antoni MS, DC, PhD
Clinical Professor and Director of Anatomy
Department of PathobiologySophie Davis School of Biomedical Education
City University of New York;
Adjunct Associate ProfessorDivision of Pre-Clinical Sciences and
Department of Surgery
New York College of Podiatric MedicineNew York, NY, USA
Paolo De Coppi MD, PhD
Professor of Paediatric Surgery;
Head of Stem Cells and Regenerative
Medicine;
Consultant Paediatric Surgeon
Great Ormond Street Hospital
UCL Institute of Child HealthLondon, UK
John OL DeLancey MD
Norman F Miller Professor of Gynecology
Department of Obstetrics and Gynecology
Professor, Department of UrologyUniversity of Michigan Medical SchoolAnn Arbor, MI, USA
Ronald H Douglas BSc, PhD
Professor of Visual Science
Division of Optometry and Visual Science
School of Health SciencesCity University LondonLondon, UK
Barrie T Evans BDS(Hons), MB BCh,
FRCS(Eng), FRCS(Ed), FDSRCS(Eng),
FFDRCS(Ire)
Consultant Oral and Maxillofacial SurgeonSouthampton University Hospitals;Honorary Senior Lecturer in Surgery to
Southampton University Medical School;
Civilian Consultant Advisor in Oral and
Maxillofacial Surgery to the Royal Navy;
Past President, British Association of Oral
and Maxillofacial Surgeons
Southampton, UK
Juan C Fernandez-Miranda MD
Associate Professor of Neurological Surgery;
Associate Director, Center for Cranial Base
Surgery;
Director, Surgical Neuroanatomy LaboratoryUniversity of Pittsburgh Medical Center
Pittsburgh, PA, USA
Jonathan M Fishman BM BCh(Oxon),
MA(Cantab), MRCS(Eng), DOHNS, PhD
Clinical Lecturer
University College LondonLondon, UK
Roland A Fleck PhD, FRCPath, FRMS
Reader and Director, Centre for
Ultrastructural Imaging
King’s College London
London, UK
David N Furness BSc, PhD
Professor of Cellular Neuroscience
School of Life Sciences
Keele UniversityNewcastle-under-Lyme, UKSimon M Gabe MD, MSc, BSc(Hons),
MBBS, FRCP
Consultant Gastroenterologist and Honorary
Senior Lecturer;
Co-Chair of the Lennard-Jones Intestinal
Failure Unit, St Mark’s Hospital
Middlesex, UK
Andrew JT George MA, PhD, DSc,
FRCPath, FSB
Deputy Vice Chancellor (Education and
International)
Professor of Immunology
Brunel UniversityLondon, UK
Serge Ginzburg MD
Assistant Professor of Urologic Oncology
Division of UrologyFox Chase Cancer Center;Department of UrologyAlbert Einstein Medical Center
Philadelphia, PA, USA
Michael Gleeson MD, FRCS, FRACS Hons,
FDS Hons
Professor of Skull Base Surgery
University College London
The National Hospital for Neurology and
Neurosurgery
London, UK
Marc Goldstein MD, DSc(Hon), FACS
Matthew P Hardy Distinguished Professor of
Reproductive Medicine and Urology;
Surgeon-in-Chief, Male Reproductive
Medicine and Surgery
Cornell Institute for Reproductive Medicine
and Department of Urology
Weill Cornell Medical Center;
Adjunct Senior Scientist, Population Council,
Center for Biomedical Research
New York, NY, USA
Martin Götz MD, PhD
Professor, Interdisciplinary Endoscopy
Universitätsklinikum Tübingen
Tübingen, Germany
Anthony Graham BSc, PhD
Professor of Developmental Biology
MRC Centre for Developmental NeurobiologyKing’s College London
London, UK
Leonard P Griffiths MB ChB, MRCP(UK)
Registrar in Gastroenterology and General
Internal Medicine
Royal United Hospital Bath;Clinical Research Fellow
University of BathBath, UK
Paul D Griffiths PhD, FRCR, FMedSci
Professor of Radiology, Academic Unit of
Radiology
University of Sheffield
Sheffield, UK
Thomas J Guzzo MD, MPH
Vice-Chief of Urology
Assistant Professor of Urology
Perelman School of MedicineUniversity of PennsylvaniaPhiladelphia, PA, USADuane E Haines PhD, FAAAS, FAAA
Professor, Department of Neurobiology and
Anatomy;
Professor, Department of NeurologyWake Forest School of MedicineWinston-Salem, NC;Professor Emeritus, University of Mississippi
Medical Center
Jackson, MS, USA
Peter A Helliwell FIBMS, Cert BA, Cert Ed
Head Biomedical Scientist
Department of Cellular PathologyRoyal Cornwall Hospitals TrustTruro, UK
Simon Holmes BDS, MBBS, FDS, RCS,
FRCS
Professor of Craniofacial Traumatology
Department of Oral and Maxillofacial SurgeryRoyal London Hospital, Queen Mary
University of London
London, UK
Claire Hopkins MA (Oxon), FRCS
(ORLHNS), DM
Consultant Ear, Nose and Throat Surgeon
Guy’s and St Thomas’ Hospitals;
Reader in ENT
King’s College LondonLondon, UK
Benjamin M Howe MD
Assistant Professor of Radiology
Mayo Clinic
Rochester, MN, USA
Daisuke Izawa PhD
Assistant Professor, Laboratory of
Chromosome Dynamics
Institute of Molecular and Cellular
Biosciences
University of Tokyo
Tokyo, Japan
Eric Jauniaux MD, PhD, FRCOG
Professor in Obstetrics and Fetal Medicine
Academic Department of Obstetrics and
Gynaecology
UCL EGA Institute for Women’s HealthUniversity College LondonLondon, UK
Girish Jawaheer MD, FRCS(Eng),
FRCS(Paed)
Consultant Paediatric Surgeon
Great North Children’s Hospital, Royal
Victoria Infirmary
Newcastle upon Tyne NHS Foundation Trust
Newcastle upon Tyne, UK;
Formerly Specialty Tutor for Paediatric
Surgery
Royal College of Surgeons of EnglandLondon, UK;Editor for Paediatric Anatomy
Marianne Juhler MD, DMSc
Consultant NeurosurgeonCopenhagen University Hospital;Professor of NeurosurgeryUniversity Clinic of Neurosurgery
Copenhagen, Denmark
Helmut Kettenmann PhD
Professor, Charité Universitätsmedizin Berlin
Max Delbrück Center for Molecular Medicine
in the Helmholtz Society
Berlin, Germany | 16 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Contributors to the forty-first edition
xiii
Abraham L Kierszenbaum MD, PhD
Medical (Clinical) Professor Emeritus
The Sophie Davis School of Biomedical
Education
The City University of New YorkNew York, NY, USA
Alexander Kutikov MD, FACS
Associate Professor of Urologic Oncology
Department of Surgical Oncology
Fox Chase Cancer Center, Temple University
Health System
Philadelphia, PA, USA
Joey E Lai-Cheong BMedSci(Hons), MBBS,
PhD, MRCP(UK)
Consultant Dermatologist
King Edward VII Hospital (Frimley Health
NHS Foundation Trust)
Windsor, UK
Simon M Lambert BSc, MBBS, FRCS,
FRCS(Ed) (Orth)
Consultant Orthopaedic Surgeon
Shoulder and Elbow ServiceRoyal National Orthopaedic Hospital TrustStanmore, Middlesex;Honorary Senior Lecturer
Institute of Orthopaedics and
Musculoskeletal Science
University College London
London, UK
John G Lawrenson MSc(Oxon), PhD,
FCOptom
Professor of Clinical Visual Science
Division of Optometry and Visual ScienceCity University LondonLondon, UK
Nir Lipsman MD, PhD
Neurosurgery Resident
University of TorontoToronto, ON, Canada
J Peter A Lodge MD, FRCS
Professor of Surgery
Hepatobiliary and Transplant Unit
St James’s University HospitalLeeds, UK
Marios Loukas MD, PhD
Professor, Department of Anatomical
Sciences
Dean of Basic Sciences
St George’s UniversityGrenada, West Indies
Andres M Lozano MD, PhD, FRCSC, FRSC,
FCAHS
Professor and Chairman,
Dan Family Chair in NeurosurgeryUniversity of TorontoDepartment of Neurosurgery
Toronto Western Hospital
Toronto, ON, Canada
Ellen A Lumpkin PhD
Associate Professor of Somatosensory
Biology
Columbia University College of Physicians
and Surgeons
Departments of Dermatology and of
Physiology and Cellular Biophysics
New York, NY, USAPeter J Lunniss BSc, MS, FRCS
Retired Senior Lecturer
Academic Surgical Unit, St Bartholomew’s
and The London Medical College, Queen
Mary University London;
Retired Honorary Consultant Colorectal
Surgeon
Royal London and Homerton Hospitals
London, UK
the late Joseph Mathew MBBS, FMCPath,
FRCPath, CertTLHE, PGCE, CertBusStud,
FHEA
Consultant in HistopathologyDepartment of HistopathologyRoyal Cornwall Hospitals Trust
Truro, UK
John A McGrath MD, FRCP, FMedSci
Professor of Molecular Dermatology
St John’s Institute of DermatologyKing’s College London
London, UK
Stephen McHanwell BSc, PhD, FHEA, FLS,
CBiol FSB, NTF
Professor of Anatomical Sciences
School of Medical Education and School of
Dental Sciences
Faculty of Medical Sciences
Newcastle University
Newcastle upon Tyne, UK
Akanksha Mehta MD
Assistant Professor of Urology,
Emory University School of Medicine
Atlanta, GA, USA
Bryan C Mendelson FRCS(Ed), FRACS,
FACS
Head of Faculty
Melbourne Advanced Facial Anatomy
Course;
Private Practitioner, Centre for Facial Plastic
Surgery
Melbourne, VIC, Australia
Zoltán Molnár MD, DPhil
Professor of Developmental Neuroscience
Department of Physiology, Anatomy and
Genetics
University of OxfordOxford, UK
Antoon FM Moorman MD, PhD
Professor of Embryology and Molecular
Biology of Cardiovascular Diseases
Department of Anatomy, Embryology and
Physiology
University of Amsterdam, Academic Medical
Center
Amsterdam, The Netherlands
Gillian M Morriss-Kay DSc
Emeritus Professor of Developmental Anatomy
Department of Physiology, Anatomy and
Genetics
University of Oxford
Oxford, UK
Donald Moss MB, BS, FRACS, FACS
Consultant Urologist
Ballarat, VIC, AustraliaHoria Muresian MD, PhD
Head of Cardiovascular Surgery DepartmentUniversity Hospital of Bucharest
Bucharest, Romania;
Visiting Professor, St George’s University
School of Medicine
Grenada, West Indies
Robert P Myers MD, MS, FACS
Professor Emeritus
Department of UrologyMayo ClinicRochester, MN, USA
Donald A Neumann PT, PhD, FAPTA
Professor of Physical Therapy
Marquette UniversityMilwaukee, WI, USA
Dylan Myers Owen PhD
Lecturer in Experimental Biophysics
Department of Physics and Randall Division
of Cell and Molecular Biophysics
King’s College London
London, UK
Erlick AC Pereira MA(Camb), DM(Oxf),
FRCS(Eng), FRCS(NeuroSurg), MBPsS,
SFHEA
Senior Clinical Fellow in Complex Spinal
Surgery
Guy’s and St Thomas’ Hospitals
National Hospital of Neurology and
Neurosurgery
London, UK
Nancy Dugal Perrier MD, FACS
Professor, Anderson Cancer Center
Department of Surgical OncologyHouston, TX, USA
Clayton C Petro MD
General Surgery Resident;
Allen Research ScholarDepartment of General SurgeryUniversity Hospitals Case Medical Center
Cleveland, OH, USA
Andy Petroianu MD, PhD
Professor of Surgery
Department of SurgerySchool of Medicine of the Federal University
of Minas Gerais
Belo Horizonte, Minas Gerais, Brazil
Jonathon Pines PhD, FMedSci
Director of Research in Cell Division
University of CambridgeCambridge, UK
Alexander G Pitman BMedSci, MBBS,
MMed(Rad), FRANZCR, FAANMS
Professorial Fellow
Department of Anatomy and NeuroscienceUniversity of Melbourne
Parkville, VIC, Australia
Y Raja Rampersaud MD, FRCSC
Associate Professor, Division of Orthopaedic
Surgery and Neurosurgery
Department of Surgery
University of Toronto
Toronto, ON, Canada | 17 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Contributors to the forty-first edition
xivMettu Srinivas Reddy MS, FRCS, PhD
Consultant Surgeon
Institute of Liver Disease and TransplantationGlobal Health City
Chennai, India
Mohamed Rela MS, FRCS, DSc
Director, Institute of Liver Disease and
Transplantation
Global Health City, Chennai, India;
Professor of Liver Surgery
Institute of Liver Studies, King’s College
Hospital
London, UK
Guilherme C Ribas MD
Professor of Surgery
University of São Paulo Medical School;Neurosurgeon, Hospital Israelita Albert
Einstein
São Paulo, Brazil;Visiting Professor of Neurosurgery
University of Virginia
Charlottesville, VA, USA
Bruce Richard MBBS, MS, FRCS(Plast)
Consultant Plastic Surgeon
Birmingham Children’s Hospital
Birmingham, UK
Michael J Rosen MD
Professor of Surgery;
Chief, Division of Gastrointestinal and
General Surgery
Case Medical Center
Case Western Reserve University
University Hospitals of ClevelandCleveland, OH, USA
Alistair C Ross MB, FRCS
Consultant Orthopaedic Surgeon
The Bath Clinic
Bath, UK
Stefano Sandrone PhD student
Neuroscientist, NatBrainLab
Sackler Institute of Translational
Neurodevelopment
Department of Forensic and
Neurodevelopmental Sciences
Institute of Psychiatry, Psychology and
Neuroscience
King’s College London
London, UK
Martin Scaal PhD
Professor of Anatomy and Developmental
Biology
Institute of Anatomy II
University of Cologne
Cologne, Germany
Paul N Schofield MA, DPhil
University Reader in Biomedical Informatics
Department of Physiology, Development and
Neuroscience
University of CambridgeCambridge, UK
Nadav Schwartz MD
Assistant Professor, Maternal Fetal Medicine
Department of Obstetrics and Gynecology,
Perelman School of Medicine
University of PennsylvaniaPhiladelphia, PA, USA
Vikram Sharma BSc(Hons), MBBS(Lon),
MRCS(Eng), PG(Cert)
Clinical Research Fellow
Nuffield Department of Surgical SciencesUniversity of OxfordOxford, UKRichard M Sharpe BSc, Msc, PhD, FRSE
Professor and Group LeaderMRC Centre for Reproductive HealthThe Queen’s Medical Research Institute
University of Edinburgh
Edinburgh, UK
Mohammadali M Shoja MD
Research Fellow
Department of Neurosurgery
University of Alabama at Birmingham
Birmingham, AL, USA
Victoria L Shone PhD, MSc, BSc
Research Associate in Developmental
Biology
King’s College London
London, UK
Monty Silverdale MD, PhD, FRCP
Consultant Neurologist
Salford Royal NHS Foundation Trust;
Honorary Senior Lecturer in Neuroscience
University of ManchesterManchester, UK
Jonathan MW Slack MA, PhD, FMedSci
Emeritus Professor, University of Bath
Bath, UK;
Emeritus Professor, University of Minnesota,Minneapolis, MN, USA
Ariana L Smith MD
Associate Professor of Urology
Director of Pelvic Medicine and
Reconstructive Surgery
Penn Medicine, Perelman School of
Medicine
University of Pennsylvania Health SystemPhiladelphia, PA, USA
Carl H Snyderman MD, MBA
Professor of Otolaryngology and
Neurological Surgery
Co-Director, UPMC Center for Cranial Base
Surgery
University of Pittsburgh Medical Center
Pittsburgh, PA, USA
Jane C Sowden PhD
Professor of Developmental Biology and
Genetics
UCL Institute of Child Health
University College London
London, UK
Robert J Spinner MD
Chair, Department of Neurologic Surgery
Burton M Onofrio, MD Professor of
Neurosurgery;
Professor of Orthopedics and AnatomyMayo ClinicRochester, MN, USA
Jonathan D Spratt MA(Cantab), FRCS(Eng),
FRCR
Clinical Director of Diagnostic Radiology
City Hospitals Sunderland NHS Foundation
Trust
Sunderland, UK;Visiting Professor of AnatomyFormer anatomy examiner for the Royal
College of Surgeons of England and Royal College of Radiologists
Editor for Imaging Anatomy
Jacob Bertram Springborg MD, PhD
Consultant Neurosurgeon;Associate Professor of NeurosurgeryUniversity Clinic of NeurosurgeryCopenhagen University HospitalCopenhagen, DenmarkSusan Standring MBE, DSc, FKC, Hon FAS,
Hon FRCS
Emeritus Professor of AnatomyKing’s College London
London, UK
Ido Strauss MD, PhD
Department of Neurosurgery
Toronto Western HospitalToronto, ON, Canada
Mark D Stringer BSc, MS, FRCP, FRCS,
FRCS(Ed), FRACS
Professor of Paediatric Surgery
Christchurch Hospital;Honorary Professor of Anatomy
University of Otago
Dunedin, New Zealand
Paul H Sugarbaker MD, FACS, FRCS
Medical Director, Center for Gastrointestinal
Malignancies;
Chief, Program in Peritoneal Surface Oncology
MedStar Washington Hospital Center
Washington, DC, USA
Cheryll Tickle MA, PhD
Emeritus Professor
Department of Biology and Biochemistry
University of Bath
Bath, UK
Kimberly S Topp PT, PhD, FAAA
Professor and Chair, Department of Physical
Therapy and Rehabilitation Science
Professor, Department of Anatomy
University of California, San FranciscoSan Francisco, CA, USA
Drew A Torigian MD, MA, FSAR
Associate Professor of Radiology;
Clinical Director, Medical Image Processing
Group
Department of Radiology
Hospital of the University of PennsylvaniaPhiladelphia, PA, USA
David Tosh BSc, PhD
Professor of Stem Cell and Regenerative
Biology
Centre for Regenerative Medicine
University of BathBath, UK
R Shane Tubbs MS, PA-C, PhD
Chief Scientific Officer
Seattle Science Foundation, Seattle, WA,
USA;
Professor of Human Gross and
Developmental Anatomy
Department of Anatomical SciencesSt. George’s University, Grenada, West
Indies;
ProfessorCentre of Anatomy and Human IdentificationUniversity of Dundee, Dundee, UK
Richard Tunstall BMedSci, PhD, PGCLTHE
FHEA
Head of Clinical Anatomy and Imaging
Warwick Medical SchoolUniversity of Warwick, UK;
University Hospitals Coventry and
Warwickshire NHS Trust
Coventry, UK;
Visiting Professor of Anatomy
St George’s University, Grenada, West Indies
Editor for Surface Anatomy | 18 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Contributors to the forty-first edition
xv
Andry Vleeming PhD
Professor of Clinical Anatomy
University of New EnglandCollege of Osteopathic Medicine
Biddeford, ME, USA;
Department of Rehabilitation Sciences and
Physiotherapy
Faculty of Medicine and Health SciencesGhent UniversityGhent, Belgium
Jan Voogd MD
Emeritus Professor of Anatomy
Department of NeuroscienceErasmus Medical CenterRotterdam, The Netherlands
Bart Wagner BSc, CSci, FIBMS, Dip Ult
Path.
Chief Biomedical Scientist
Electron Microscopy UnitHistopathology Department
Royal Hallamshire Hospital (Sheffield
Teaching Hospitals)
Sheffield, UKGary Warburton DDS, MD, FDSRCS, FACS
Associate Professor;
Program Director and Division ChiefOral and Maxillofacial Surgery
University of Maryland Dental School
Baltimore, MD, USA
Jeremy PT Ward BSc, PhD
Head of Department of Physiology;
Professor of Respiratory Cell Physiology
Department of Physiology
King’s College LondonLondon, UK
John C Watkinson MSc, MS, FRCS, DLO
Consultant ENT, Head and Neck and Thyroid
Surgeon
Queen Elizabeth Hospital
University of Birmingham NHS TrustBirmingham, UK
Alan J Wein MD, PhD(Hon), FACS
Founders Professor and Chief of Urology
Director, Urology Residency ProgramPenn Medicine, Perelman School of
Medicine
University of Pennsylvania Health SystemPhiladelphia, PA, USACaroline B Wigley BSc, PhD
University of Exeter Medical SchoolExeter, UKEditor for Cell and Tissue Microstructure
Frank H Willard PhD
Professor of AnatomyUniversity of New England College of
Osteopathic Medicine
Biddeford, Maine, USA
Chin-Ho Wong MBBS, MRCS(Ed),
MMed(Surg), FAMS(Plast Surg)
Plastic Surgeon, Private Practice
Singapore
Stephanie J Woodley PhD, MSc, BPhty
Senior Lecturer
Department of AnatomyUniversity of OtagoDunedin, New Zealand | 19 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
e5
HISTORICAL INTRODUCTION
required to operate on real patients, or on soldiers injured at Sebastopol
or some other battlefield. The book they planned together was a practi -
cal one, designed to encourage youngsters to study anatomy, help them pass exams, and assist them as budding surgeons. It was not simply an
anatomy textbook, but a guide to dissecting procedure, and to the major
operations.
Gray and Carter belonged to a generation of anatomists ready to
infuse the study of human anatomy with a new, and respectable, scien -
tificity. Disreputable aspects of the profession’s history, acquired during the days of body-snatching, were assiduously being forgotten. The
Anatomy Act of 1832 had legalized the requisition of unclaimed bodies
from workhouse and hospital mortuaries, and the study of anatomy
(now with its own Inspectorate) was rising in respectability in Britain.
The private anatomy schools that had flourished in the Regency period
were closing their doors, and the major teaching hospitals were erecting
new, purpose-built dissection rooms (Richardson 2000).
The best-known student works when Gray and Carter had qualified
were probably Erasmus Wilson’s Anatomist’s Vade Mecum , and Elements
of Anatomy by Jones Quain. Both works were small – pocket-sized – but Quain came in two thick volumes. Both Quain’s and Wilson’s works
were good books in their way, but their small pages of dense type, and
even smaller illustrations, were somewhat daunting, seeming to demand
much nose-to-the-grindstone effort from the reader.
The planned new textbook’s dimensions and character were serious
matters. Pocket manuals were commercially successful because they
appealed to students by offering much knowledge in a small compass.
But pocket-sized books had button-sized illustrations. Knox’s Manual
of Human Anatomy, for example, was a good book, but was only 6 inches
by 4 (15 × 10 cm) and few of its illustrations occupied more than one-
third of a page. Gray and Carter must have discussed this matter between themselves, and with Gray’s publisher, JW Parker & Son, before deci-
sions were taken about the size and girth of the new book, and espe -
cially the size of its illustrations. While Gray and Carter were working on the book, a new edition of Quain’s was published; this time it was
a ‘triple-decker’ – in three volumes – of 1740 pages in all.
The two men were earnestly engaged for the following 18 months
in work for the new book. Gray wrote the text, and Carter created the illustrations; all the dissections were undertaken jointly. Their working
days were long – all the hours of daylight, eight or nine hours at a
stretch – right through 1856, and well into 1857. We can infer from the
warmth of Gray’s appreciation of Carter in his published acknowledge-
ments that their collaboration was a happy one.
The Author gratefully acknowledges the great services he has derived in
the execution of this work, from the assistance of his friend, Dr. H. V.
Carter, late Demonstrator of Anatomy at St George’s Hospital. All the
drawings from which the engravings were made, were executed by him.
(Gray 1858)
With all the dissections done, and Carter’s inscribed wood-blocks at the engravers, Gray took six months’ leave from his teaching at St George’s
to work as a personal doctor for a wealthy family. It was probably as
good a way as any to get a well-earned break from the dissecting room
and the dead-house (Nicol 2002).
Carter sat the examination for medical officers in the East India
Company, and sailed for India in the spring of 1858, when the book
was still in its proof stages. Gray had left a trusted colleague, Timothy
Holmes, to see it through the press. Holmes’s association with the first
edition would later prove vital to its survival. Gray looked over the final galley proofs, just before the book finally went to press.
THE FIRST EDITION
The book Gray and Carter had created together, Anatomy, Descriptive
and Surgical, appeared at the very end of August 1858, to immediate Gray’s Anatomy is now on its way to being 160 years old. The book is a
rarity in textbook publishing in having been in continuous publication
on both sides of the Atlantic Ocean, since 1858. One and a half centu -
ries is an exceptionally long era for a textbook. Of course, the volume now is very different from the one Mr Henry Gray first created with his
colleague Dr Henry Vandyke Carter, in mid-Victorian London. In this introductory essay, I shall explain the long history of Gray’s, from those
Victorian days right up to today.
The shortcomings of existing anatomical textbooks probably
impressed themselves on Henry Gray when he was still a student at St George’s Hospital Medical School, near London’s Hyde Park Corner, in
the early 1840s. He began thinking about creating a new anatomy
textbook a decade later, while war was being fought in the Crimea. New
legislation was being planned that would establish the General Medical
Council (1858) to regulate professional education and standards.
Gray was twenty-eight years old, and a teacher himself at St George’s.
He was very able, hard-working and highly ambitious, already a Fellow
of the Royal Society, and of the Royal College of Surgeons. Although
little is known about his personal life, his was a glittering career so far,
achieved while he served and taught on the hospital wards and in the
dissecting room (Fig. 1) (Anon 1908).
Gray shared the idea for the new book with a talented colleague on
the teaching staff at St George’s, Henry Vandyke Carter, in November
1855. Carter was from a family of Scarborough artists, and was himself a clever artist and microscopist. He had produced fine illustrations for
Gray’s scientific publications before, but could see that this idea was a
much more complex project. Carter recorded in his diary:
Little to record. Gray made proposal to assist by drawings in bringing
out a Manual for students: a good idea but did not come to any plan …
too exacting, for would not be a simple artist (Carter 1855).
Neither of these young men was interested in producing a pretty book,
or an expensive one. Their purpose was to supply an affordable, accurate
teaching aid for people like their own students, who might soon be
Fig. 1 Henry Gray (1827–1861) is shown here in the foreground, seated
by the feet of the cadaver. The photograph was taken by a medical
student, Joseph Langhorn. The room is the dissecting room of St
George’s Hospital Medical School in Kinnerton Street, London. Gray is shown surrounded by staff and students. When the photo was taken, on 27 March 1860, Carter had left St George’s, to become Professor of Anatomy and Physiology at Grant Medical College, in Bombay (nowadays Mumbai). The second edition of Gray’s Anatomy was in its proof stages,
to appear in December 1860. Gray died just over a year later, in June 1861, at the height of his powers.
| 20 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Historical introduction
e6Fig. 2 Henry Vandyke Carter (1831–1897). Carter was appointed
Honorary Surgeon to Queen Victoria in 1890.
acclaim. Reviews in The Lancet and the British Medical Journal were
highly complimentary, and students flocked to buy.
It is not difficult to understand why it was a runaway success. Gray’s
Anatomy knocked its competitors into a cocked hat. It was considerably
smaller and more slender than the doorstopper with which modern
readers are familiar. The book held well in the hand, it felt substantial,
and it contained everything required. To contemporaries, it was small
enough to be portable, but large enough for decent illustrations: ‘royal
octavo’ – 912 × 6 inches (24 × 15 cm) – about two-thirds of modern A4
size. Its medium-size, single-volume format was far removed from
Quain, yet double the size of Knox’s Manual.
Simply organized and well designed, the book explains itself confi -
dently and well; the clarity and authority of the prose are manifest. But
what made it unique for its day was the outstanding size and quality
of the illustrations. Gray thanked the wood engravers Butterworth and
Heath for the ‘great care and fidelity’ they had displayed in the engrav-
ings, but it was really to Carter that the book owed its extraordinary
success.
The beauty of Carter’s illustrations resides in their diagrammatic
clarity, quite atypical for their time. The images in contemporary
anatomy books were usually ‘proxy-labelled’: dotted with tiny numbers
or letters (often hard to find or read) or bristling with a sheaf of num -
bered arrows, referring to a key situated elsewhere, usually in a footnote, which was sometimes so lengthy it wrapped round on to the following
page. Proxy labels require the reader’s eye to move to and fro: from the
structure to the proxy label to the legend and back again. There was
plenty of scope for slippage, annoyance and distraction. Carter’s illustra -
tions, by contrast, unify name and structure, enabling the eye to assimi -
late both at a glance. We are so familiar with Carter’s images that it is
hard to appreciate how incredibly modern they must have seemed in
1858. The volume made human anatomy look new, exciting, accessible
and do-able.
The first edition was covered in a brown bookbinder’s cloth embossed
all over in a dotted pattern, and with a double picture-frame border. Its
spine was lettered in gold blocking:
sense of calamity. The grand old medical man Sir Benjamin Brodie, Sergeant-Surgeon to the Queen, and the great supporter of Gray to
whom Anatomy had been dedicated, cried forlornly: ‘Who is there to
take his place?’ (Anon 1908).
But old JW Parker ensured the survival of Gray’s by inviting Timothy
Holmes, the doctor who had helped proof-read the first edition, and who had filled Gray’s shoes at the medical school, to serve as Editor for
the next edition. Other long-running anatomy works, such as Quain,
remained in print in a similar way, co-edited by other hands (Quain
1856).
Holmes (1825–1907) was another gifted St George’s man, a scholar -
ship boy who had won an exhibition to Cambridge, where his brilliance
was recognized. Holmes was a Fellow of the Royal College of Surgeons
at 28. John Parker junior had commissioned him to edit A System of
Surgery (1860–64), an important essay series by distinguished surgeons on subjects of their own choosing. Many of Holmes’s authors remain
important figures, even today: John Simon, James Paget, Henry Gray,
Ernest Hart, Jonathan Hutchinson, Brown-Séquard and Joseph Lister.
Holmes had lost an eye in an operative accident, and he had a gruff
manner that terrified students, yet he published a lament for young
Parker that reveals him capable of deep feeling (Holmes 1860).
John Parker senior’s heart, however, was no longer in publishing.
His son’s death had closed down the future for him. The business, with
all its stocks and copyrights, was sold to Messrs Longman. Parker retired
to the village of Farnham, where he later died.
With Holmes as editor, and Longman as publisher, the immediate
future of Gray’s Anatomy was assured. The third edition appeared in
1864 with relatively few changes, Gray’s estate receiving the balance of his royalty after Holmes was paid £100 for his work.
THE MISSING OBITUARY
Why no obituary appeared for Henry Gray in Gray’s Anatomy is curious.
Gray had referred to Holmes as his ‘friend’ in the preface to the first
edition, yet it would also be true to say that they were rivals. Both had just applied for a vacant post at St George’s, as Assistant Surgeon. Had Gray lived, it is thought that Holmes may not have been appointed, despite his seniority in age (Anon 1908).
Later commentators have suggested, as though from inside knowl -
edge, that Holmes’s ‘proof-reading’ included improving Gray’s writing … with ‘DESCRIPTIVE AND SURGICAL’ in small capitals underneath.
Gray’s Anatomy is how it has been referred to ever since. Carter was given
credit with Gray on the book’s title page for undertaking all the dissec -
tions on which the book was based, and sole credit for all the illustra -
tions, though his name appeared in a significantly smaller type, and he
was described as the ‘Late Demonstrator in Anatomy at St George’s Hospital’ rather than being given his full current title, which was Profes -
sor of Anatomy and Physiology at Grant Medical College, Bombay. Gray was still only a Lecturer at St George’s and he may have been aware that
his words had been upstaged by the quality of Carter’s anatomical
images. He need not have worried: Gray is the famous name on the
spine of the book.
Gray was paid £150 for every thousand copies sold. Carter never
received a royalty payment, just a one-off fee at publication, which may
have allowed him to purchase the long-wished-for microscope he took
with him to India (Fig. 2).
The first edition print-run of 2000 copies sold out swiftly. A parallel
edition was published in the United States in 1859, and Gray must have
been deeply gratified to have to revise an enlarged new English edition
in 1859–60, though he was surely saddened and worried by the death
of his publisher, John Parker junior, at the young age of 40, while the
book was going through the press. The second edition came out in the
December of 1860 and it too sold like hot cakes, as indeed has every
subsequent edition.
The following summer, in June 1861, at the height of his powers and
full of promise, Henry Gray died unexpectedly at the age of only 34.
Gray had contracted smallpox while nursing his nephew. A new strain
of the disease was more virulent than the one with which Gray had
been vaccinated as a child; the disease became confluent, and Gray died
in a matter of days.
Within months, the whole country would be pitched into mourning
for the death of Prince Albert. The creative era over which he had pre -
sided – especially the decade that had flowered since the Great Exhibi -
tion of 1851 – would be history.
THE BOOK SURVIVES
Anatomy Descriptive and Surgical could have died too. With Carter in
India, the death of Gray, so swiftly after that of the younger Parker, might have spelled catastrophe. Certainly, at St George’s there was a GRAY’S
ANATOMY | 21 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Historical introduction
e7
were not as yet perfected, and in any case could not provide the bold
simplicity of line required for a book like Gray’s, which depended so
heavily on clear illustration and clear lettering. Recognizing the inferior -
ity of half-tone illustrations by comparison with Carter’s wood-engraved
originals, Pick and Howden courageously decided to jettison the
second-rate half-tones altogether. Most of the next edition’s illustrations
were either Carter’s, or old supplementary illustrations inspired by his
work, or newly commissioned wood engravings or line drawings,
intended ‘to harmonize with Carter’s original figures’ . They successfully
emulated Carter’s verve. Having fewer pages and lighter paper, the 1905
(sixteenth edition) weighed less than its predecessor, at 4 lb 1 1 oz/2.1 kg.
Typographically, the new edition was superb.
Howden took over as sole editor in 1909 (seventeenth edition) and
immediately stamped his personality on Gray’s. He excised ‘Surgical’
from the title, changing it to Anatomy Descriptive and Applied, and
removed Carter’s name altogether. He also instigated the beginnings of an editorial board of experts for Gray’s, by adding to the title page ‘Notes
on Applied Anatomy’ by AJ Jex-Blake and W Fedde Fedden, both St George’s men. For the first time, the number of illustrations exceeded
one thousand. Howden was responsible for the significant innovation
of a short historical note on Henry Gray himself, nearly 60 years after
his death, which included a portrait photograph (1918, twentieth
edition).
THE NOMENCLATURE CONTROVERSY
Howden’s era, and that of his successor TB Johnston (of Guy’s), was
overshadowed by a cloud of international controversy concerning ana -
tomical terminology. European anatomists were endeavouring to stand -
ardize anatomical terms, often using Latinate constructions, a move
resisted in Britain and the United States. Gray’s became mired in these
debates for over 20 years. The attempt to be fair to all sides by using multiple terms doubtless generated much confusion amongst students,
until a working compromise was at last arrived at in 1955 (thirty-second
edition, 1958).
Johnston oversaw the second retitling of the book (in 1938, twenty-
seventh edition): it was now, officially, Gray’s Anatomy, finally ending
the fiction that it had ever been known as anything else. Gray’s suffered
from paper shortages and printing difficulties in World War II, but suc -
cessive editions nevertheless continued to grow in size and weight, while illustrations were replaced and added as the text was revised.
Between Howden’s first sole effort (1909, seventeenth edition) and
Johnston’s last edition (1958, thirty-second edition), Gray’s expanded
by over 300 pages – from 1296 to 1604 pages, and almost 300 addi -
tional illustrations brought the total to over 1300. Johnston also intro -
duced X-ray plates (1938) and, in 1958 (thirty-second edition), electron micrographs by AS Fitton-Jackson, one of the first occasions on which
a woman was credited with a contribution to Gray’s. Johnston felt com -
pelled to mention that she was ‘a blood relative of Henry Gray himself’, perhaps by way of mitigation.
AFTER WORLD WAR II
The editions of Gray’s issued in the decades immediately following the
Second World War give the impression of intellectual stagnation. Steady expansion continued in an almost formulaic fashion, with the insertion
of additional detail. The central historical importance of innovation in
the success of Gray’s seems to have been lost sight of by its publishers
and editors – Johnston (1930–1958, twenty-fourth to thirty-second editions), J Whillis (co-editor with Johnston, 1938–1954), DV Davies
(1958–1967, thirty-second to thirty-fourth editions) and F Davies
(co-editor with DV Davies 1958–1962, thirty-second to thirty-third
editions). Gray’s had become so pre-eminent that perhaps complacency
crept in, or editors were too daunted or too busy to confront the ‘massive undertaking’ of a root and branch revision (Tansey 1995). The
unexpected deaths of three major figures associated with Gray’s in this
era, James Whillis, Francis Davies and David Vaughan Davies – each of whom had been ready to take the editorial reins – may have contributed
to retarding the process. The work became somewhat dull.
KEY EDITION: 1973
DV Davies had recognized the need for modernization, but his unex -
pected death left the work to other hands. Two Professors of Anatomy
at Guy’s, Roger Warwick and Peter Williams, the latter of whom had been involved as an indexer for Gray’s for several years, regarded it as
an honour to fulfill Davies’s intentions.
Their thirty-fifth edition of 1973 was a significant departure from
tradition. Over 780 pages (of 1471) were newly written, almost a third style. This could be a reflection of Holmes’s own self-regard, but there
may be some truth in it. There can be no doubt that, as Editor of seven
subsequent editions of Gray’s Anatomy (third to ninth editions, 1864–
1880), Holmes added new material, and had to correct and compress passages, but it is also possible that, back in 1857, Gray’s original
manuscript had been left in a poor state for Holmes to sort out. In other
works, Gray’s writing style was lucid, but he always seems to have paid
a copyist to transcribe his work prior to submission. The original manu -
script of Gray’s Anatomy, sadly, has not survived, so it is impossible to
be sure how much of the finished version had actually been written by
Holmes.
It may be that Gray’s glittering career, or perhaps the patronage that
unquestionably advanced it, created jealousies among his colleagues,
or that there was something in Gray’s manner that precluded affection,
or that created resentments among clever social inferiors like Carter and
Holmes, especially if they felt their contributions to his brilliant career
were not given adequate credit. Whatever the explanation, no reference
to Gray’s life or death appeared in Gray’s Anatomy itself until the twen -
tieth century (Howden et al 1918).
A SUCCESSION OF EDITORS
Holmes expanded areas of the book that Gray himself had developed
in the second edition (1860), notably in ‘general’ anatomy (histology)
and ‘development’ (embryology). In Holmes’s time as Editor, the
volume grew from 788 pages in 1864 to 960 in 1880 (ninth edition),
with the histological section paginated separately in roman numerals
at the front of the book. Extra illustrations were added, mainly from
other published sources.
The connections with Gray and Carter, and with St George’s, were
maintained with the appointment of the next editor, T. Pickering Pick,
who had been a student at St George’s in Gray’s time. From 1883 (tenth
edition) onwards, Pick kept up with current research, rewrote and inte -
grated the histology and embryology into the volume, dropped Holmes from the title page, removed Gray’s preface to the first edition, and
added bold subheadings, which certainly improved the appearance and
accessibility of the text. Pick said he had ‘tried to keep before himself
the fact that the work is intended for students of anatomy rather than
for the Scientific Anatomist’ (thirteenth edition, 1893).
Pick also introduced colour printing (in 1887, eleventh edition) and
experimented with the addition of illustrations using the new printing
method of half-tone dots: for colour (which worked) and for new black-
and-white illustrations (which did not). Half-tone shades of grey com -
pared poorly with Carter’s wood engravings, still sharp and clear by comparison.
What Henry Vandyke Carter made of these changes is a rich topic
for speculation. He returned to England in 1888, having retired from
the Indian Medical Service, full of honours – Deputy Surgeon General,
and in 1890, he was made Honorary Surgeon to Queen Victoria. Carter
had continued researching throughout his clinical medical career in
India, and became one of India’s foremost bacteriologists/tropical
disease specialists before there was really a name for either discipline.
Carter made some important discoveries, including the fungal cause of
mycetoma, which he described and named. He was also a key figure in
confirming scientifically in India some major international discoveries,
such as Hansen’s discovery of the cause of leprosy, Koch’s discovery of
the organism causing tuberculosis, and Laveran’s discovery of the organ -
ism that causes malaria. Carter married late in life, and his wife was left with two young children when he died in Scarborough in 1897, aged
65. Like Gray, he received no obituary in the book.
When Pick was joined on the title page by Robert Howden (a profes -
sional anatomist from the University of Durham) in 1901 (fifteenth
edition), the volume was still easily recognizable as the book Gray and
Carter had created. Although many of Carter’s illustrations had been
revised or replaced, many others still remained. Sadly, though, an entire
section (embryology) was again separately paginated, as its revision had
taken longer than anticipated. Gray’s had grown, seemingly inexorably,
and was now quite thick and heavy: 1244 pages, weighing 5 lb
8 oz/2.5 kg. Both co-editors, and perhaps also its publisher, were dis -
satisfied with it.
KEY EDITION: 1905
Serious decisions were taken well in advance of the next edition, which
turned out to be Pick’s last with Howden. Published 50 years after Gray had first suggested the idea to Carter, the 1905 (sixteenth) edition was a landmark one.
The period 1880–1930 was a difficult time for anatomical illustra-
tion, because the new techniques of photo-lithography and half-tone | 22 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Historical introduction
e8had developed a distinct character of its own in the interval), and sold
extremely well there (Williams and Warwick 1973).
The influence of the Warwick and Williams edition was forceful and
long-lasting, and set a new pattern for the following quarter-century.
As has transpired several times before, wittingly or unwittingly, a new
editor was being prepared for the future: Dr Susan Standring (of
Guy’s), who created the new bibliography for the 1973 edition of
Gray’s, went on to serve on the editorial board, and has served as
Editor-in-Chief for the last two editions before this one (2005–2008,
thirty-ninth and fortieth editions). Both editions are important for dif -
ferent reasons.
For the thirty-ninth edition, the entire content of Gray’s was reorgan-
ized, from systematic to regional anatomy. This great sea-change was not just organizational but historic, because, since its outset, Gray’s had
prioritized bodily systems, with subsidiary emphasis on how the systems interweave in the regions of the body. Professor Standring
explained that this regional change of emphasis had long been asked
for by readers and users of Gray’s, and that new imaging techniques in
our era have raised the clinical importance of local anatomy (Standring 2005). The change was facilitated by an enormous collective effort on
the part of the editorial team and the illustrators. The subsequent and
current editions consolidate that momentous change. (See Table 1.)
Table 1 Gray’s Anatomy Editions
Edition Date Author/Editor(s) Publisher Title
1st 1858 Henry Gray JW Parker & Son Anatomy Descriptive and Surgical
The drawings by Henry Vandyke Carter. The dissections jointly by
the author and Dr Carter
2nd 1860 Henry Gray JW Parker & Son
3rd 1864 T Holmes Longman
4th 1866 T Holmes Longman
5th 1869 T Holmes Longman
6th 1872 T Holmes Longman
7th 1875 T Holmes Longman
8th 1877 T Holmes Longman
9th 1880 T Holmes Longman
10th 1883 TP Pick Longman
11th 1887 TP Pick Longman
12th 1890 TP Pick Longman
13th 1893 TP Pick Longman
Gray’s preface removed
14th 1897 TP Pick Longman
15th 1901 TP Pick & R Howden Longman
16th 1905 TP Pick & R Howden Longman
17th 1909 Robert Howden Longman Anatomy Descriptive and Applied
Notes on applied anatomy by AJ Jex-Blake & W Fedde Fedden
18th 1913 Robert Howden & Blake & Fedden Longman
19th 1916 Robert Howden & Blake & Fedden Longman
20th 1918 Robert Howden & Blake & Fedden Longman
First edition ever to feature a photograph and obituary of Henry Gray
21st 1920 Robert Howden Longman
Notes on applied anatomy by AJ Jex-Blake & John Clay
22nd 1923 Robert Howden Longman
Notes on applied anatomy by John Clay & John D Lickley
23rd 1926 Robert Howden Longman
24th 1930 TB Johnston Longman
25th 1932 TB Johnston Longman
26th 1935 TB Johnston Longman
27th 1938 TB Johnston & J Whillis Longman Gray’s Anatomy
28th 1942 TB Johnston & J Whillis Longman
29th 1946 TB Johnston & J Whillis Longman
30th 1949 TB Johnston & J Whillis Longman
31st 1954 TB Johnston & J Whillis Longman
32nd 1958 TB Johnston & DV Davies & F Davies Longman
33rd 1962 DV Davies & F Davies Longman
34th 1967 DV Davies & RE Coupland Longman
35th 1973 Peter L Williams & Roger Warwick Longman
With a separate volume: Functional Neuroanatomy of Man – being the
neurology section of Gray’s Anatomy. 35th edition, 1975
36th 1980 Roger Warwick & Peter L Williams Churchill Livingstone
37th 1989 Peter L Williams Churchill Livingstone
38th 1995 Peter L Williams & Editorial Board Churchill Livingstone
39th 2005 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice
40th 2008 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice
41st 2015 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practiceof the illustrations were newly commissioned, and the illustration cap -
tions were freshly written throughout. With a complete re-typesetting
of the text in larger double-column pages, a new index and the innova -
tion of a bibliography, this edition of Gray’s looked and felt quite unlike
its 1967 (thirty-fourth edition) predecessor, and much more like its
modern incarnation.
This 1973 edition departed from earlier volumes in other significant
ways. The editors made explicit their intention to try to counter the
impetus towards specialization and compartmentalization in twentieth-
century medicine, by embracing and attempting to reintegrate the com -
plexity of the available knowledge. Warwick and Williams openly renounced the pose of omniscience adopted by many textbooks, believ -
ing it important to accept and mention areas of ignorance or uncer -
tainty. They shared with the reader the difficulty of keeping abreast in
the sea of research, and accepted with a refreshing humility the impos-
sibility of fulfilling their own ambitious programme.
Warwick and Williams’s 1973 edition had much in common with
Gray and Carter’s first edition. It was bold and innovative – respectful
of its heritage, while also striking out into new territory. It was visually
attractive and visually informative. It embodied a sense of a treasury of
information laid out for the reader (Williams and Warwick 1973). It
was published simultaneously in the United States (the American Gray’s | 23 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Historical introduction
e9
Howden R, Jex-Blake AJ, Fedde Fedden W (eds) 1918 Gray’s Anatomy, 20th
ed. London: Longman.
Lewis H Sinclair 1925 Arrowsmith. New York: Harcourt Brace; p. 4.
Nicol KE 2002 Henry Gray of St George’s Hospital: a Chronology. London:
published by the author.
Quain J 1856 Elements of Anatomy. Ed. by Sharpey W, Ellis GV. London:
Walton & Maberly.
Richardson R 2000 Death, Dissection and the Destitute. Chicago: Chicago
University Press; pp. 193–249, 287, 357.
Richardson R 2008 The Making of Mr Gray’s Anatomy. Oxford: Oxford
University Press.
Standring S (ed.) 2005 Preface. In: Gray’s Anatomy, 39th ed. Elsevier:
London.
Tansey EM 1995 A brief history of Gray’s Anatomy. In: Gray’s Anatomy, 38th
ed. London: Churchill Livingstone.
Williams PL, Warwick R (eds.) 1973 Preface. In: Gray’s Anatomy, 35th ed.
London: Churchill Livingstone.THE DOCTORS’ BIBLE
Neither Gray nor Carter, the young men who – by their committed hard
work between 1856 and 1858 – created the original Gray’s Anatomy,
would have conceived that so many years after their deaths their book would not only be a household name, but also be regarded as a work
of such pre-eminent importance that a novelist half a world away would
rank it as cardinal – alongside the Bible and Shakespeare – to a doctor’s
education (Sinclair Lewis 1925, Richardson 2008). From this forty-first
edition of Gray’s Anatomy, we can look back to appraise the long-term
value of their efforts. We can discern how the book they created tri -
umphed over its competitors, and has survived pre-eminent. Gray’s is a
remarkable publishing phenomenon. Although the volume now looks
quite different to the original, and contains so much more, its kinship
with the Gray’s Anatomy of 1858 is easily demonstrable by direct descent,
every edition updated by Henry Gray’s successor. Works are rare indeed that have had such a long history of continuous publication on both
sides of the Atlantic, and such a useful one.
Ruth Richardson, MA, DPhil, FRHistS
Senior Visiting Research Fellow, Centre for Life-Writing Research,
King’s College London;
Affiliated Scholar in the History and Philosophy of Science,
University of Cambridge, UK
REFERENCES
Anon 1908 Henry Gray. St George’s Hospital Gazette 16:49–54.
Carter HV 1855 Diary. Wellcome Western Manuscript 5818; 25 Nov.Gray H 1858 Preface. In: Anatomy: Descriptive and Surgical. London: JW
Parker & Son.
Holmes T (ed.) 1860 I: Preface. In: A System of Surgery. London: JW Parker
& Son.ACKNOWLEDGEMENTS
For their assistance while I was undertaking the research for this essay,
I should like to thank the Librarians and Archivists and Staff at the
British Library, Society of Apothecaries, London School of Hygiene and
Tropical Medicine, Royal College of Surgeons, Royal Society of Medi -
cine, St Bride Printing Library, St George’s Hospital Tooting, Scarbor -
ough City Museum and Art Gallery, University of Reading, Wellcome
Institute Library, Westminster City Archives and Windsor Castle; and
the following individuals: Anne Bayliss, Gordon Bell, David Buchanan,
Dee Cook, Arthur Credland, Chris Hamlin, Victoria Killick, Louise King,
Keith Nicol, Sarah Potts, Mark Smalley, and Nallini Thevakarrunai.
Above all, my thanks to Brian Hurwitz, who has read and advised on
the evolving text. | 24 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
xviANATOMICAL NOMENCLATURE
with the median plane; although often employed, ‘parasagittal’ is there -
fore redundant and should not be used. The coronal (frontal) plane is
orthogonal to the median plane and divides the body into anterior
(front) and posterior (back). The horizontal (transverse) plane is
orthogonal to both median and sagittal planes. Radiologists refer to
transverse planes as (trans)axial; convention dictates that axial anatomy
is viewed as though looking from the feet towards the head.
Structures nearer the head are superior, cranial or (sometimes)
cephalic (cephalad), whereas structures closer to the feet are inferior;
caudal is most often used in embryology to refer to the hind end of the
embryo. Medial and lateral indicate closeness to the median plane,
medial being closer than lateral; in the anatomical position, the little
finger is medial to the thumb, and the great toe is medial to the little
toe. Specialized terms may also be used to indicate medial and lateral.
Thus, in the upper limb, ulnar and radial are used to mean medial and
lateral, respectively; in the lower limb, tibial and fibular (peroneal) are
used to mean medial and lateral, respectively. Terms may be based on
embryological relationships; the border of the upper limb that includes
the thumb, and the border of the lower limb that includes the great toe
are the pre-axial borders, whilst the opposite borders are the post-axial
borders. Various degrees of obliquity are acknowledged using com-
pound terms, e.g. posterolateral.
When referring to structures in the trunk and upper limb, we have
freely used the synonyms anterior, ventral, flexor, palmar and volar, and
posterior, dorsal and extensor. We recognize that these synonyms are
not always satisfactory, e.g. the extensor aspect of the leg is anterior with
respect to the knee and ankle joints, and superior in the foot and digits;
the plantar (flexor) aspect of the foot is inferior. Dorsal (dorsum) and
ventral are terms used particularly by embryologists and neuroanato -
mists; they therefore feature most often in Sections 2 and 3.
Distal and proximal are used particularly to describe structures in
the limbs, taking the datum point as the attachment of the limb to the trunk (sometimes referred to as the root), such that a proximal structure
is closer to the attachment of the limb than a distal structure. However,
proximal and distal are also used in describing branching structures,
e.g. bronchi, vessels and nerves. External (outer) and internal (inner)
refer to the distance from the centre of an organ or cavity, e.g. the layers
of the body wall, or the cortex and medulla of the kidney. Superficial
and deep are used to describe the relationships between adjacent struc -
tures. Ipsilateral refers to the same side (of the body, organ or structure), bilateral to both sides, and contralateral to the opposite side.
Teeth are described using specific terms that indicate their relation -
ship to their neighbours and to their position within the dental arch;
these terms are described on page 517.Anatomy is the study of the structure of the body. Conventionally, it is
divided into topographical (macroscopic or gross) anatomy (which
may be further divided into regional anatomy, surface anatomy, neuro -
anatomy, endoscopic and imaging anatomy); developmental anatomy (embryogenesis and subsequent organogenesis); and the anatomy of
microscopic and submicroscopic structure (histology).
Anatomical language is one of the fundamental languages of medi -
cine. The unambiguous description of thousands of structures is impos -
sible without an extensive and often highly specialized vocabulary. Ideally, these terms, which are often derived from Latin or Greek,
should be used to the exclusion of any other, and eponyms should be
avoided. In reality, this does not always happen. Many terms are ver -
nacularized and, around the world, synonyms and eponyms still abound in the literature, in medical undergraduate classrooms and in
clinics. The Terminologia Anatomica,
1 drawn up by the Federative Com-
mittee on Anatomical Terminology (FCAT) in 1998, continues to serve
as our reference source for the terminology for macroscopic anatomy,
and the text of the forty-first edition of Gray’s Anatomy is almost entirely
TA-compliant. However, where terminology is at variance with, or, more likely, is not included in, the TA, the alternative term used either is cited
in the relevant consensus document or position paper, or enjoys wide -
spread clinical usage. Synonyms and eponyms are given in parentheses on first usage of a preferred term and not shown thereafter in the text;
an updated list of eponyms and short biographical details of the clini -
cians and anatomists whose names are used in this way is available in the e-book for reference purposes (see Preface , p. ix, for further discus -
sion of the use of eponyms).
PLANES, DIRECTIONS AND
RELATIONSHIPS
To avoid ambiguity, all anatomical descriptions assume that the body
is in the conventional ‘anatomical position’, i.e. standing erect and
facing forwards, upper limbs by the side with the palms facing forwards,
and lower limbs together with the toes facing forwards (Fig. 1). Descrip -
tions are based on four imaginary planes – median, sagittal, coronal and horizontal – applied to a body in the anatomical position. The
median plane passes longitudinally through the body and divides it
into right and left halves. The sagittal plane is any vertical plane parallel
1Terminologia Anatomica (1998) is the joint creation of the Federative Committee on
Anatomical Terminology (FCAT) and the Member Associations of the Interna -
tional Federation of Associations of Anatomists (IFAA). | 25 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
AnAtomic Al nomencl Ature
xvii
Fig. 1 The terminology widely used in descriptive anatomy. Abbreviations shown on arrows: AD, adduction; AB, abduction; FLEX, flexion (of the thigh at
the hip joint); EXT, extension (of the leg at the knee joint).
LEFT LATERAL ASPECTPOSTERIOR ASPECTSUPERIOR ASPECT
Lateral
InversionEversionMedial (internal) rotationLateral (external) rotationPronationSupinationDistallyProximally
DistallyProximallyMedial (internal) rotationLateral (external) rotationMedialPosterior or dorsalAnterior or ventralCoronal plane
Median or sagittal plane
Transverse or horizontal planeInferior or caudal
Superior or cranial
INFERIOR ASPECTANTERIOR ASPECTRIGHT LATERAL ASPECT | 26 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
xviiiBIBLIOGRAPHY OF SELECTED TITLES
Haaga JR, Dogra VS, Forsting M, Gilkeson RC, Ha KH, Sundaram M
2009 CT and MR Imaging of the Whole Body, 5th ed. St Louis:
Elsevier, Mosby.
Lasjaunias P, Berenstein A, ter Brugge K 2001 Surgical Neuroangio
graphy, vol 1. Clinical Vascular Anatomy and Variations, 2nd ed. Berlin, New York: Springer.
Meyers MA 2000 Dynamic Radiology of the Abdomen: Normal and
Pathologic Anatomy, 5th ed. New York: Springer.
Pomeranz SJ 1992 MRI Total Body Atlas. Cincinnati: MRI EFI.
Spratt JD, Salkowski LR, Weir J, Abrahams PH 2010 Imaging Atlas of Human Anatomy, 4th ed. London: Elsevier, Mosby.
Sutton D, Reznek R, Murfitt J 2002 Textbook of Radiology and Imaging,
7th ed. Edinburgh: Elsevier, Churchill Livingstone.
Whaites E, Drage N 2013 Essentials of Dental Radiography and Radiol
ogy, 5th ed. Edinburgh: Elsevier, Churchill Livingstone.Wicke L 2004 Atlas of Radiologic Anatomy, 7th ed. Philadelphia:
Elsevier, WB Saunders.
CLINICAL
Birch R 2010 Surgical Disorders of the Peripheral Nerves, 2nd ed. Edin
burgh: Elsevier, Churchill Livingstone.Bogduk N 2012 Clinical and Radiological Anatomy of the Lumbar
Spine, 5th ed. Edinburgh: Elsevier, Churchill Livingstone.
Borges AF 1984 Relaxed skin tension lines (RSTL) versus other skin
lines. Plast Reconstr Surg 73:144–50.
Burnand KG, Young AE, Lucas JD, Rowlands B, Scholefield J 2005 The
New Aird’s Companion in Surgical Studies, 3rd ed. Edinburgh: Elsevier, Churchill Livingstone.
Canale ST, Beaty JH 2012 Campbell’s Operative Orthopaedics, 12th ed.
Philadelphia: Elsevier, Mosby.
Cormack GC, Lamberty BGH 1994 The Arterial Anatomy of Skin Flaps,
2nd ed. Edinburgh: Elsevier, Churchill Livingstone.
Cramer GD, Darby SA 2013 Clinical Anatomy of the Spine, Spinal Cord,
and ANS, 3rd ed. MO: Elsevier, Mosby.
Dyck PJ, Thomas PK 2005 Peripheral Neuropathy: 2 Volume Set with
Expert Consult Basic, 4th ed. Philadelphia: Elsevier, WB Saunders.
Ellis H, Mahadevan V 2013 Clinical Anatomy: Applied Anatomy for
Students and Junior Doctors, 13th ed. Wiley Blackwell.
Ellis H Feldman S, Harrop Griffiths W 2004 Anatomy for Anaesthetists,
8th ed. Oxford: Blackwell Science.Morris SF, Taylor GI 2013 Vascular territories. In: Neligan PC (ed.)
Plastic Surgery, vol. I. Principles, 3rd ed. London: Elsevier, Saunders.
Rosai J 201 1 Rosai and Ackerman’s Surgical Pathology, 10th ed. London:
Elsevier, Mosby.
Shah J 2012 Jatin Shah’s Head and Neck Surgery and Oncology: Expert
Consult Online and Print, 4th ed. London: Elsevier, Mosby.
Zancolli EA, Cozzi EP 1991 Atlas of Surgical Anatomy of the Hand.
Edinburgh: Elsevier, Churchill Livingstone.
CLINICAL EXAMINATION
O’Brien M 2010 Aids to the Examination of the Peripheral Nervous System, 5th ed. London: Elsevier, WB Saunders.
Lumley JSP 2008 Surface Anatomy: The Anatomical Basis of Clinical
Examination, 4th ed. Edinburgh: Elsevier, Churchill Livingstone.The following references contain information relevant to numerous
chapters in this edition. They are therefore cited here rather than at the
end of individual chapters. For an extended historical bibliography, all
references from the thirty eighth edition (which includes all references
cited in earlier editions, up to and including the thirty eighth edition)
are available in the e book that accompanies Gray’s Anatomy .
TERMINOLOGY
Federative Committee on Anatomical Terminology 1998 Terminologia Anatomica: International Anatomical Nomenclature. Stuttgart: Thieme.
Dorland WAN 201 1 Dorland’s Illustrated Medical Dictionary, 32nd ed.
Philadelphia: Elsevier, WB Saunders.
BASIC SCIENCES
Abrahams P, Spratt JD, Loukas M, van Schoor A N 2013 McMinn and
Abrahams’ Clinical Atlas of Human Anatomy: with STUDENT CONSULT Online Access, 7th ed. London: Elsevier, Mosby.
Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P 2007 Molecu
lar Biology of the Cell, 5th ed. New York: Garland Science.
Berkovitz BKB, Kirsch C, Moxham BJ, Alusi G, Cheeseman T 2002
Interactive Head and Neck. London: Primal Pictures.
Boron WF, Boulpaep E 2012 Medical Physiology: with STUDENT
CONSULT Online Access, 2nd ed. Philadelphia: Elsevier, WB Saunders.
Crossman AR 2014 Neuroanatomy: An Illustrated Colour Text, 5th ed.
Edinburgh: Elsevier, Churchill Livingstone.
Fitzgerald MD 201 1 Clinical Neuroanatomy and Neuroscience: with
STUDENT CONSULT Online Access, 6th ed. Edinburgh: Elsevier, Saunders.
Hall JE 2010 Guyton and Hall Textbook of Medical Physiology: with
STUDENT CONSULT Online Access, 12th ed. Philadelphia: Elsevier, Saunders.
Kerr JB 2010 Functional Histology, 2nd ed. London: Elsevier, Mosby.
Kierszenbaum AL 2014 Histology and Cell Biology: An Introduction to
Pathology, 4th ed. St Louis: Elsevier, Mosby.
Lowe JS, Anderson PG 2014 Stevens & Lowe’s Human Histology,
4th ed. London: Elsevier, Mosby.
Male D, Brostoff J, Roth D, Roitt I 2012 Immunology: with STUDENT
CONSULT Online Access, 8th ed. London: Elsevier, Mosby.
Moore KL, Persaud TVN, Torchia MG 2015 Before We Are Born: Essen
tials of Embryology and Birth Defects, 9th ed. St Louis: Elsevier.
Pollard TD, Earnshaw WC 2007 Cell Biology: with STUDENT CONSULT
Access, 2nd ed. Philadelphia: Elsevier, WB Saunders.
Salmon M 1994 Anatomic Studies: Book 1 Arteries of the Muscles of
the Extremities and the Trunk, Book 2 Arterial Anastomotic Pathways of the Extremities. Ed. by Taylor GI, Razaboni RM. St Louis: Quality Medical.
Young B, O’Dowd G, Woodford P 2013 Wheater’s Functional Histology:
A Text and Colour Atlas, 6th ed. Edinburgh: Elsevier, Churchill Livingstone.
IMAGING AND RADIOLOGY/RADIOLOGICAL
ANATOMY
Butler P, Mitchell AWM, Healy JC 201 1 Applied Radiological Anatomy,
2nd ed. New York: Cambridge University Press.
Ellis H, Logan BM, Dixon AK 2007 Human Sectional Anatomy: Pocket
Atlas of Body Sections, CT and MRI Images, 3rd ed. CRC Press.
| 27 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
4SECTION 1
CHAPTER 1 Basic structure and function of cells
Epithelial cells rarely operate independently of each other and com-
monly form aggregates by adhesion, often assisted by specialized inter -
cellular junctions. They may also communicate with each other either
by generating and detecting molecular signals that diffuse across inter -
cellular spaces, or more rapidly by generating interactions between membrane-bound signalling molecules. Cohesive groups of cells con -
stitute tissues, and more complex assemblies of tissues form functional systems or organs.
Most cells are between 5 and 50 µm in diameter: e.g. resting lym-
phocytes are 6 µm across, red blood cells 7.5 µm and columnar epithe -
lial cells 20 µm tall and 10 µm wide (all measurements are approximate).
Some cells are much larger than this: e.g. megakaryocytes of the bone
marrow and osteoclasts of the remodelling bone are more than 200 µm
in diameter. Neurones and skeletal muscle cells have relatively extended
shapes, some of the former being over 1 m in length.
CELLULAR ORGANIZATION
Each cell is contained within its limiting plasma membrane, which encloses the cytoplasm. All cells, except mature red blood cells, also
contain a nucleus that is surrounded by a nuclear membrane or enve -
lope (see Fig. 1.1; Fig. 1.2). The nucleus includes: the genome of the
cell contained within the chromosomes; the nucleolus; and other sub -
nuclear structures. The cytoplasm contains cytomembranes and several membrane-bound structures, called organelles, which form separate CELL STRUCTURE
GENERAL CHARACTERISTICS OF CELLS
The shapes of mammalian cells vary widely depending on their interac -
tions with each other, their extracellular environment and internal
structures. Their surfaces are often highly folded when absorptive or
transport functions take place across their boundaries. Cell size is
limited by rates of diffusion, either that of material entering or leaving
cells, or that of diffusion within them. Movement of macromolecules
can be much accelerated and also directed by processes of active trans -
port across the plasma membrane and by transport mechanisms within the cell. According to the location of absorptive or transport functions,
apical microvilli (Fig. 1.1) or basolateral infoldings create a large
surface area for transport or diffusion.
Motility is a characteristic of most cells, in the form of movements
of cytoplasm or specific organelles from one part of the cell to another.
It also includes: the extension of parts of the cell surface such as pseu -
dopodia, lamellipodia, filopodia and microvilli; locomotion of entire cells, as in the amoeboid migration of tissue macrophages; the beating
of flagella or cilia to move the cell (e.g. in spermatozoa) or fluids overly -
ing it (e.g. in respiratory epithelium); cell division; and muscle contrac -
tion. Cell movements are also involved in the uptake of materials from
their environment (endocytosis, phagocytosis) and the passage of large
molecular complexes out of cells (exocytosis, secretion).
Fig . 1 .1 The main structural components and internal organization of a generalized cell . Plasma membraneActin filaments
Vesicle
Golgi apparatusIntermediate
filamentsMitochondrion
Smooth endoplasmic
reticulum
Rough endoplasmic
reticulumPeroxisomes
CytosolSurface invaginationSurface projections
(cilia, microvilli)
Cell junctions
Desmosome
Microtubules
Centriole pairNuclear envelope
Nucleus
RibosomeNucleolus
Lysosomes
Cell surface foldsNuclear pore | 31 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
5
CHaPTER 1
charides and polysaccharides are bound either to proteins (glycopro -
teins) or to lipids (glycolipids), and project mainly into the extracellular
domain (Fig. 1.3).
In the electron microscope, membranes fixed and contrasted by
heavy metals such as osmium tetroxide appear in section as two densely
stained layers separated by an electron-translucent zone – the classic
unit membrane. The total thickness of each layer is about 7.5 nm. The
overall thickness of the plasma membrane is typically 15 nm. Freeze-
fracture cleavage planes usually pass along the hydrophobic portion of the bilayer, where the hydrophobic tails of phospholipids meet, and
split the bilayer into two leaflets. Each cleaved leaflet has a surface and
a face. The surface of each leaflet faces either the extracellular surface
(ES) or the intracellular or protoplasmic (cytoplasmic) surface (PS). The
extracellular face (EF) and protoplasmic face (PF) of each leaflet are
artificially produced during membrane splitting. This technique has
also demonstrated intramembranous particles embedded in the lipid
bilayer; in most cases, these represent large transmembrane protein
molecules or complexes of proteins. Intramembranous particles are
distributed asymmetrically between the two half-layers, usually adher -
ing more to one half of the bilayer than to the other. In plasma mem -
branes, the intracellular leaflet carries most particles, seen on its face
(the PF). Where they have been identified, clusters of particles usually
represent channels for the transmembrane passage of ions or molecules
between adjacent cells (gap junctions).
Biophysical measurements show the lipid bilayer to be highly fluid,
allowing diffusion in the plane of the membrane. Thus proteins are able
to move freely in such planes unless anchored from within the cell.
Membranes in general, and the plasma membrane in particular, form
boundaries selectively limiting diffusion and creating physiologically
distinct compartments. Lipid bilayers are impermeable to hydrophilic
solutes and ions, and so membranes actively control the passage of ions
and small organic molecules such as nutrients, through the activity of
membrane transport proteins. However, lipid-soluble substances can pass directly through the membrane so that, for example, steroid hor -
mones enter the cytoplasm freely. Their receptor proteins are either cytosolic or nuclear, rather than being located on the cell surface.
Plasma membranes are able to generate electrochemical gradients
and potential differences by selective ion transport, and actively take up or export small molecules by energy-dependent processes. They also provide surfaces for the attachment of enzymes, sites for the receptors and distinct compartments within the cytoplasm. Cytomembranes
include the rough and smooth endoplasmic reticulum and Golgi appa-
ratus, as well as vesicles derived from them. Organelles include lyso -
somes, peroxisomes and mitochondria. The nucleus and mitochondria are enclosed by a double-membrane system; lysosomes and peroxi -
somes have a single bounding membrane. There are also non-membranous structures, called inclusions, which lie free in the cytosolic
compartment. They include lipid droplets, glycogen aggregates and pig -
ments (e.g. lipofuscin). In addition, ribosomes and several filamentous protein networks, known collectively as the cytoskeleton, are found in
the cytosol. The cytoskeleton determines general cell shape and sup -
ports specialized extensions of the cell surface (microvilli, cilia, flag -
ella). It is involved in the assembly of specific structures (e.g. centrioles)
and controls cargo transport in the cytoplasm. The cytosol contains
many soluble proteins, ions and metabolites.
Plasma membrane
Cells are enclosed by a distinct plasma membrane, which shares fea -
tures with the cytomembrane system that compartmentalizes the cyto -
plasm and surrounds the nucleus. All membranes are composed of lipids (mainly phospholipids, cholesterol and glycolipids) and pro -
teins, in approximately equal ratios. Plasma membrane lipids form a
lipid bilayer, a layer two molecules thick. The hydrophobic ends of each
lipid molecule face the interior of the membrane and the hydrophilic
ends face outwards. Most proteins are embedded within, or float in, the lipid bilayer as a fluid mosaic. Some proteins, because of extensive hydrophobic regions of their polypeptide chains, span the entire width of the membrane (transmembrane proteins), whereas others are only superficially attached to the bilayer by lipid groups. Both are integral (intrinsic) membrane proteins, as distinct from peripheral (extrinsic) membrane proteins, which are membrane-bound only through their association with other proteins. Carbohydrates in the form of oligosac-
Fig . 1 .2 The structural organization and some principal organelles of a
typical cell . This example is a ciliated columnar epithelial cell from human
nasal mucosa . The central cell, which occupies most of the field of
view, is closely apposed to its neighbours along their lateral plasma
membranes . Within the apical junctional complex, these membranes form
a tightly sealed zone (tight junction) that isolates underlying tissues from,
in this instance, the nasal cavity . Abbreviations: AJC, apical junctional
complex; APM, apical plasma membrane; C, cilia; Cy, cytoplasm; EN,
euchromatic nucleus; LPM, lateral plasma membrane; M, mitochondria;
MV, microvilli; N, nucleolus . (Courtesy of Dr Bart Wagner, Histopathology
Department, Sheffield Teaching Hospitals, UK .)
C MV
M
Cy
LPM
N
ENMAPMAJCV M C
M
Cy
LPM
N
ENMAPMAJC
Fig . 1 .3 The molecular organization of the plasma membrane, according
to the fluid mosaic model of membrane structure . Intrinsic or integral
membrane proteins include diffusion or transport channel complexes,
receptor proteins and adhesion molecules . These may span the thickness
of the membrane (transmembrane proteins) and can have both
extracellular and cytoplasmic domains . Transmembrane proteins have
hydrophobic zones, which cross the phospholipid bilayer and allow the
protein to ‘float’ in the plane of the membrane . Some proteins are
restricted in their freedom of movement where their cytoplasmic domains
are tethered to the cytoskeleton . Receptor
protein
Lipid bilayer
appearancein electronmicroscopeInternal
(intracellular)
surfaceCarbohydrateresidues
TransmembraneproteinIntrinsic
membrane
protein
Transport
or diffusion
channelExtrinsic
proteinTransmembrane
pore complex
of proteins
External
(extracellular)
surface
Polar end ofphospholipidNon-polar tailof phospholipid
Cytoskeletalelement | 32 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
5.e1
CHaPTER 1
Combinations of biochemical, biophysical and biological tech -
niques have revealed that lipids are not homogenously distributed in
membranes, but that some are organized into microdomains in the bilayer, called ‘detergent-resistant membranes’ or lipid ‘rafts’, rich in sphingomyelin and cholesterol. The ability of select subsets of proteins
to partition into different lipid microdomains has profound effects on
their function, e.g. in T-cell receptor and cell–cell signalling. The highly organized environment of the domains provides a signalling, trafficking and membrane fusion environment. | 33 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
6SECTION 1
abundant proteins; SER is abundant in steroid-producing cells and
muscle cells. A variant of the endoplasmic reticulum in muscle cells is
the sarcoplasmic reticulum, involved in calcium storage and release for
muscle contraction. For further reading on the endoplasmic reticulum,
see Bravo et al (2013).
Smooth endoplasmic reticulum
The smooth endoplasmic reticulum (see Fig. 1.4) is associated with
carbohydrate metabolism and many other metabolic processes, includ -
ing detoxification and synthesis of lipids, cholesterol and steroids. The membranes of the smooth endoplasmic reticulum serve as surfaces for
the attachment of many enzyme systems, e.g. the enzyme cytochrome
P450, which is involved in important detoxification mechanisms and
is thus accessible to its substrates, which are generally lipophilic. The
membranes also cooperate with the rough endoplasmic reticulum
and the Golgi apparatus to synthesize new membranes; the protein, carbohydrate and lipid components are added in different structural
compartments. The smooth endoplasmic reticulum in hepatocytes con -
tains the enzyme glucose-6-phosphatase, which converts glucose-6-
phosphate to glucose, a step in gluconeogenesis.
Rough endoplasmic reticulum
The rough endoplasmic reticulum is a site of protein synthesis; its
cytosolic surface is studded with ribosomes ( Fig. 1.5E). Ribosomes only
bind to the endoplasmic reticulum when proteins targeted for secretion begin to be synthesized. Most proteins pass through its membranes and
accumulate within its cisternae, although some integral membrane pro -
teins, e.g. plasma membrane receptors, are inserted into the rough endoplasmic reticulum membrane, where they remain. After passage
from the rough endoplasmic reticulum, proteins remain in membrane-
bound cytoplasmic organelles such as lysosomes, become incorporated
into new plasma membrane, or are secreted by the cell. Some carbohy -
drates are also synthesized by enzymes within the cavities of the rough endoplasmic reticulum and may be attached to newly formed protein
(glycosylation). Vesicles are budded off from the rough endoplasmic
reticulum for transport to the Golgi as part of the protein-targeting
mechanism of the cell.
Ribosomes, polyribosomes
and protein synthesis
Ribosomes are macromolecular machines that catalyse the synthesis of
proteins from amino acids; synthesis and assembly into subunits takes
place in the nucleolus and includes the association of ribosomal RNA
(rRNA) with ribosomal proteins translocated from their site of synthesis
in the cytoplasm. The individual subunits are then transported into the
cytoplasm, where they remain separate from each other when not
actively synthesizing proteins. Ribosomes are granules approximately
25 nm in diameter, composed of rRNA molecules and proteins assem -
bled into two unequal subunits. The subunits can be separated by their sedimentation coefficients (S) in an ultracentrifuge into larger 60S and
smaller 40S components. These are associated with 73 different pro -
teins (40 in the large subunit and 33 in the small), which have structural and enzymatic functions. Three small, highly convoluted rRNA strands
(28S, 5.8S and 5S) make up the large subunit, and one strand (18S) is
in the small subunit.
A typical cell contains millions of ribosomes. They may form groups
(polyribosomes or polysomes) attached to messenger RNA (mRNA),
which they translate during protein synthesis for use outside the system
of membrane compartments, e.g. enzymes of the cytosol and cytoskel -
etal proteins. Some of the cytosolic products include proteins that can be inserted directly into (or through) membranes of selected organelles,
such as mitochondria and peroxisomes. Ribosomes may be attached to
the membranes of the rough endoplasmic reticulum (see Fig. 1.5E).
In a mature polyribosome, all the attachment sites of the mRNA are
occupied as ribosomes move along it, synthesizing protein according
to its nucleotide sequence. Consequently, the number and spacing of
ribosomes in a polyribosome indicate the length of the mRNA mole -
cule and hence the size of the protein being made. The two subunits have separate roles in protein synthesis. The 40S subunit is the site of
attachment and translation of mRNA. The 60S subunit is responsible
for the release of the new protein and, where appropriate, attachment
to the endoplasmic reticulum via an intermediate docking protein that
directs the newly synthesized protein through the membrane into the cisternal space.
Golgi apparatus (Golgi complex)
The Golgi apparatus is a distinct cytomembrane system located near the nucleus and the centrosome. It is particularly prominent in secretory cells and can be visualized when stained with silver or other metallic
of external signals, including hormones and other ligands, and sites for
the recognition and attachment of other cells. Internally, plasma mem -
branes can act as points of attachment for intracellular structures, in particular those concerned with cell motility and other cytoskeletal
functions. Cell membranes are synthesized by the rough endoplasmic
reticulum in conjunction with the Golgi apparatus.
Cell coat (glycocalyx)
The external surface of a plasma membrane differs structurally from
internal membranes in that it possesses an external, fuzzy, carbohydrate-
rich coat, the glycocalyx. The cell coat forms an integral part of the
plasma membrane, projecting as a diffusely filamentous layer 2–20 nm
or more from the lipoprotein surface. The cell coat is composed of the
carbohydrate portions of glycoproteins and glycolipids embedded in
the plasma membrane (see Fig. 1.3).
The precise composition of the glycocalyx varies with cell type; many
tissue- and cell type-specific antigens are located in the coat, including
the major histocompatibility complex of the immune system and, in
the case of erythrocytes, blood group antigens. Therefore, the glycocalyx
plays a significant role in organ transplant compatibility. The glycocalyx
found on apical microvilli of enterocytes, the cells forming the lining
epithelium of the intestine, consists of enzymes involved in the diges -
tive process. Intestinal microvilli are cylindrical projections (1–2 µm
long and about 0.1 µm in diameter) forming a closely packed layer
called the brush border that increases the absorptive function of
enterocytes.
Cytoplasm
Compartments and functional organization
The cytoplasm consists of the cytosol, a gel-like material enclosed by
the cell or plasma membrane. The cytosol is made up of colloidal pro -
teins such as enzymes, carbohydrates and small protein molecules, together with ribosomes and ribonucleic acids. The cytoplasm contains
two cytomembrane systems, the endoplasmic reticulum and Golgi
apparatus, as well as membrane-bound organelles (lysosomes, peroxi -
somes and mitochondria), membrane-free inclusions (lipid droplets, glycogen and pigments) and the cytoskeleton. The nuclear contents,
the nucleoplasm, are separated from the cytoplasm by the nuclear envelope.
Endoplasmic reticulum
The endoplasmic reticulum is a system of interconnecting membrane-lined channels within the cytoplasm ( Fig. 1.4). These channels take
various forms, including cisternae (flattened sacs), tubules and vesicles.
The membranes divide the cytoplasm into two major compartments.
The intramembranous compartment, or cisternal space, is where secre -
tory products are stored or transported to the Golgi complex and cell exterior. The cisternal space is continuous with the perinuclear space.
Structurally, the channel system can be divided into rough or granu -
lar endoplasmic reticulum (RER), which has ribosomes attached to its
outer, cytosolic surface, and smooth or agranular endoplasmic reticu-
lum (SER), which lacks ribosomes. The functions of the endoplasmic
reticulum vary greatly and include: the synthesis, folding and transport
of proteins; synthesis and transport of phospholipids and steroids; and
storage of calcium within the cisternal space and regulated release into
the cytoplasm. In general, RER is well developed in cells that produce
Fig . 1 .4 Smooth endoplasmic reticulum with associated vesicles . The
dense particles are glycogen granules . (Courtesy of Rose Watson, Cancer
Research UK .)
| 34 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
6.e1
CHaPTER 1
The glycocalyx plays a significant role in maintenance of the integrity
of tissues and in a wide range of dynamic cellular processes, e.g. serving
as a vascular permeability barrier and transducing fluid shear stress to
the endothelial cell cytoskeleton (Weinbaum et al 2007). Disruption of
the glycocalyx on the endothelial surface of large blood vessels precedes
inflammation, a conditioning factor of atheromatosis (e.g. deposits of
cholesterol in the vascular wall leading to partial or complete obstruc -
tion of the vascular lumen).
Protein synthesis on ribosomes may be suppressed by a class of RNA
molecules known as small interfering RNA (siRNA) or silencing RNA.
These molecules are typically 20–25 nucleotides in length and bind (as
a complex with proteins) to specific mRNA molecules via their comple -
mentary sequence. This triggers the enzymatic destruction of the mRNA or prevents the movement of ribosomes along it. Synthesis of the
encoded protein is thus prevented. Their normal function may have
antiviral or other protective effects; there is also potential for developing
artificial siRNAs as a therapeutic tool for silencing disease-related genes. | 35 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
7
CHaPTER 1
Fig . 1 .5 The Golgi apparatus and functionally related organelles . A, Golgi apparatus (G) adjacent to the nucleus (N) (V, vesicle) . B, A large residual body
(tertiary lysosome) in a cardiac muscle cell (M, mitochondrion) . C, The functional relationships between the Golgi apparatus and associated cellular
structures . D, A three-dimensional reconstruction of the Golgi apparatus in a pancreatic β cell showing stacks of Golgi cisternae from the cis-face (pink)
and cis-medial cisternae (red, green) to the trans-Golgi network (blue, yellow, orange–red); immature proinsulin granules (condensing vesicles) are
shown in pale blue and mature (crystalline) insulin granules in dark blue . The flat colour areas represent cut faces of cisternae and vesicles . E, Rough
endoplasmic reticulum (R), associated with the Golgi apparatus (G) . (D, Courtesy of Dr Brad Marsh, Institute for Molecular Bioscience, University of
Queensland, Brisbane . A,B,E From human tissue, courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .)
M
Phagocytic pathway Secretory pathway Receptor-mediated endocytosis Membrane recycling
Early endosome
Late endosome
Secondary lysosome
Residual body
cis-Golgi network
Rough endoplasmic
reticulumGolgi cisternaeVesicle shuttling
between cisternaeLysosomal
fusionClathrin-coated pit
trans-Golgi networkA B
C
D EG
VN
G
G
RG
G | 36 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
8SECTION 1
Endocytic (internalization) pathway
The endocytic pathway begins at the plasma membrane and ends in
lysosomes involved in the degradation of the endocytic cargo through
the enzymatic activity of lysosomal hydrolases. Endocytic cargo is
internalized from the plasma membrane to early endosomes and
then to late endosomes. Late endosomes transport their cargo to lyso -
somes, where the cargo material is degraded following fusion and mixing of contents of endosomes and lysosomes. Early endosomes
derive from endocytic vesicles (clathrin-coated vesicles and caveolae).
Once internalized, endocytic vesicles shed their coat of adaptin and
clathrin, and fuse to form an early endosome, where the receptor
molecules release their bound ligands. Membrane and receptors from
the early endosomes can be recycled to the cell surface as exocytic
vesicles.
Clathrin-dependent endocytosis occurs at specialized patches of
plasma membrane called coated pits; this mechanism is also used to
internalize ligands bound to surface receptor molecules and is also
termed receptor-mediated endocytosis. Caveolae (little caves) are struc -
turally distinct pinocytotic vesicles most widely used by endothelial and smooth muscle cells, when they are involved in transcytosis, signal
transduction and possibly other functions. In addition to late endo -
somes, lysosomes can also fuse with phagosomes, autophagosomes
and plasma membrane patches for membrane repair. Lysosomal hydro -
lases process or degrade exogenous materials (phagocytosis or hetero -
phagy) as well as endogenous material (autophagy). Phagocytosis consists of the cellular uptake of invading pathogens, apoptotic cells
and other foreign material by specialized cells. Lysosomes are numerous
in actively phagocytic cells, e.g. macrophages and neutrophil granulo-
cytes, in which lysosomes are responsible for destroying phagocytosed
particles, e.g. bacteria. In these cells, the phagosome, a vesicle poten -
tially containing a pathogenic microorganism, may fuse with several lysosomes.
Autophagy involves the degradation and recycling within an
autophagosome of cytoplasmic components that are no longer needed,
including organelles. The assembly of the autophagosome involves
several proteins, including autophagy-related (Atg) proteins, as well as
Hsc70 chaperone, that translocate the substrate into the lysosome (Boya
et al 2013). Autophagosomes sequester cytoplasmic components and
then fuse with lysosomes without the participation of a late endosome.
The 26S proteasome (see below) is also involved in cellular degradation
but autophagy refers specifically to a lysosomal degradation–recycling
pathway. Autophagosomes are seen in response to starvation and cell
growth.
Late endosomes receive lysosomal enzymes from primary lysosomes
derived from the Golgi apparatus after late endosome–lysosome mem -
brane tethering and fusion followed by diffusion of lysosomal contents into the endosomal lumen. The pH inside the fused hybrid organelle,
now a secondary lysosome, is low (about 5.0) and this activates lyso -
somal acid hydrolases to degrade the endosomal contents. The products of hydrolysis either are passed through the membrane into the cytosol,
or may be retained in the secondary lysosome. Secondary lysosomes
may grow considerably in size by vesicle fusion to form multivesicular
bodies, and the enzyme concentration may increase greatly to form
large lysosomes ( Fig. 1.5B).
Lysosomes
Lysosomes are membrane-bound organelles 80–800 nm in diameter,
often with complex inclusions of material undergoing hydrolysis (sec -
ondary lysosomes). Two classes of proteins participate in lysosomal
function: soluble acid hydrolases and integral lysosomal membrane
proteins. Each of the 50 known acid hydrolases (including proteases,
lipases, carbohydrases, esterases and nucleases) degrades a specific sub -
strate. There are about 25 lysosomal membrane proteins participating in the acidification of the lysosomal lumen, protein import from the
cytosol, membrane fusion and transport of degradation products to the
cytoplasm. Material that has been hydrolysed within secondary lyso -
somes may be completely degraded to soluble products, e.g. amino acids, which are recycled through metabolic pathways. However, degra -
dation is usually incomplete and some debris remains. A debris-laden vesicle is called a residual body or tertiary lysosome (see Fig. 1.5B), and
may be passed to the cell surface, where it is ejected by exocytosis;
alternatively, it may persist inside the cell as an inert residual body. Considerable numbers of residual bodies can accumulate in long-lived cells, often fusing to form larger dense vacuoles with complex lamellar inclusions. As their contents are often darkly pigmented, this may change the colour of the tissue; e.g. in neurones, the end-product of lysosomal digestion, lipofuscin (neuromelanin or senility pigment), gives ageing brains a brownish-yellow colouration. Lysosomal enzymes
salts. Traffic between the endoplasmic reticulum and the Golgi appara -
tus is bidirectional and takes place via carrier vesicles derived from the
donor site that bud, tether and fuse with the target site.
Golgins are long coiled-coil proteins attached to the cytoplasmic
surface of cisternal membranes, forming a fibrillar matrix surrounding
the Golgi apparatus to stabilize it; they have a role in vesicle trafficking
(for further reading on golgins, see Munro 201 1). The Golgi apparatus
has several functions: it links anterograde and retrograde protein and lipid flow in the secretory pathway; it is the site where protein and lipid
glycosylation occurs; and it provides membrane platforms to which
signalling and sorting proteins bind.
Ultrastructurally, the Golgi apparatus (Fig. 1.5A) displays a contin-
uous ribbon-like structure consisting of a stack of several flattened
membranous cisternae, together with clusters of vesicles surrounding
its surfaces. Cisternae differ in enzymatic content and activity. Small
transport vesicles from the rough endoplasmic reticulum are received
at one face of the Golgi stack, the convex cis-face (entry or forming
surface). Here, they deliver their contents to the first cisterna in the series by membrane fusion. From the edges of this cisterna, the protein
is transported to the next cisterna by vesicular budding and then
fusion, and this process is repeated across medial cisternae until the
final cisterna at the concave trans-face (exit or condensing surface) is
reached. Here, larger vesicles are formed for delivery to other parts of the cell.
The cis-Golgi and trans-Golgi membranous networks form an inte -
gral part of the Golgi apparatus. The cis-Golgi network is a region of
complex membranous channels interposed between the rough endo -
plasmic reticulum and the Golgi cis-face, which receives and transmits
vesicles in both directions. Its function is to select appropriate proteins synthesized on the rough endoplasmic reticulum for delivery by vesicles
to the Golgi stack, while inappropriate proteins are shuttled back to the
rough endoplasmic reticulum.
The trans-Golgi network, at the other side of the Golgi stack, is also
a region of interconnected membrane channels engaged in protein
sorting. Here, modified proteins processed in the Golgi cisternae are
packaged selectively into vesicles and dispatched to different parts of
the cell. The packaging depends on the detection, by the trans-Golgi
network, of particular amino-acid signal sequences, leading to their enclosure in membranes of appropriate composition that will further
modify their contents, e.g. by extracting water to concentrate them
(vesicles entering the exocytosis pathway) or by pumping in protons to
acidify their contents (lysosomes destined for the intracellular sorting
pathway).
Within the Golgi stack proper, proteins undergo a series of sequen -
tial chemical modifications by Golgi resident enzymes synthesized
in the rough endoplasmic reticulum. These include: glycosylation (changes in glycosyl groups, e.g. removal of mannose, addition of
N-acetylglucosamine and sialic acid); sulphation (addition of sulphate
groups to glycosaminoglycans); and phosphorylation (addition of
phosphate groups). Some modifications serve as signals to direct pro -
teins and lipids to their final destination within cells, including lyso-somes and plasma membrane. Lipids formed in the endoplasmic
reticulum are also routed for incorporation into vesicles.
Exocytic (secretory) pathway
Secreted proteins, lipids, glycoproteins, small molecules such as amines
and other cellular products destined for export from the cell are trans -
ported to the plasma membrane in small vesicles released from the trans-face of the Golgi apparatus. This pathway either is constitutive, in
which transport and secretion occur more or less continuously, as with
immunoglobulins produced by plasma cells, or it is regulated by exter-
nal signals, as in the control of salivary secretion by autonomic neural
stimulation. In regulated secretion, the secretory product is stored tem -
porarily in membrane-bound secretory granules or vesicles. Exocytosis is achieved by fusion of the secretory vesicular membrane with the
plasma membrane and release of the vesicle contents into the extracel-
lular domain. In polarized cells, e.g. most epithelia, exocytosis occurs
at the apical plasma membrane. Glandular epithelial cells secrete into
a duct lumen, as in the pancreas, or on to a free surface, such as the
lining of the stomach. In hepatocytes, bile is secreted across a very small
area of plasma membrane forming the wall of the bile canaliculus. This
region is defined as the apical plasma membrane and is the site of
exocrine secretion, whereas secretion of hepatocyte plasma proteins into the blood stream is targeted to the basolateral surfaces facing the sinusoids. Packaging of different secretory products into appropriate vesicles takes place in the trans-Golgi network. Delivery of secretory
vesicles to their correct plasma membrane domains is achieved by sorting sequences in the cytoplasmic tails of vesicular membrane proteins. | 37 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
8.e1
CHaPTER 1
Carrier vesicles in transit from the endoplasmic reticulum to the
Golgi apparatus (anterograde transport) are coated by coat protein
complex II (COPII), whereas COPI-containing vesicles function in the
retrograde transport route from the Golgi apparatus (reviewed in Spang
(2013)).
The membranes contain specific signal proteins that may allocate
them to microtubule-based transport pathways and allow them to dock with appropriate targets elsewhere in the cell, e.g. the plasma mem -
brane in the case of secretory vesicles. Vesicle formation and budding at the trans-Golgi network involves the addition of clathrin on their
external surface, to form coated pits.
Specialized cells of the immune system, called antigen-presenting
cells, degrade protein molecules, called antigens, transported by the endocytic pathway for lysosomal breakdown, and expose their frag -
ments to the cell exterior to elicit an immune response mediated ini -
tially by helper T cells. | 38 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
9
CHaPTER 1
Mitochondria
In the electron microscope, mitochondria usually appear as round or
elliptical bodies 0.5–2.0 µm long ( Fig. 1.6), consisting of an outer
mitochondrial membrane; an inner mitochrondrial membrane, sepa-
rated from the outer membrane by an intermembrane space; cristae,
infoldings of the inner membrane that harbour ATP synthase to gener -
ate ATP; and the mitochondrial matrix, a space enclosed by the inner membrane and numerous cristae. The permeability of the two mito -
chondrial membranes differs considerably: the outer membrane is freely permeable to many substances because of the presence of large
non-specific channels formed by proteins (porins), whereas the inner
membrane is permeable to only a narrow range of molecules. The pres -
ence of cardiolipin, a phospholipid, in the inner membrane may con -
tribute to this relative impermeability.
Mitochondria are the principal source of chemical energy in most
cells. Mitochondria are the site of the citric acid (Krebs’) cycle and the
electron transport (cytochrome) pathway by which complex organic
molecules are finally oxidized to carbon dioxide and water. This process
provides the energy to drive the production of ATP from adenosine
diphosphate (ADP) and inorganic phosphate (oxidative phosphoryla -
tion). The various enzymes of the citric acid cycle are located in the mitochondrial matrix, whereas those of the cytochrome system and
oxidative phosphorylation are localized chiefly in the inner mitochon -
drial membrane.
The intermembrane space houses cytochrome c, a molecule involved
in activation of apoptosis.
The number of mitochondria in a particular cell reflects its general
energy requirements; e.g. in hepatocytes there may be as many as 2000, whereas in resting lymphocytes there are usually very few. Mature
may also be secreted – often as part of a process to alter the extracellular
matrix, as in osteoclast-mediated erosion during bone resorption. For
further reading on lysosome biogenesis, see Saftig and Klumperman
(2009).
lysosomal dysfunction
Lysosomal storage diseases (LSDs) are a consequence of lysosomal dysfunction. Approximately 60 different types of LSD have been identi -
fied on the basis of the type of material accumulated in cells (such as
mucopolysaccharides, sphingolipids, glycoproteins, glycogen and lipo -
fuscins). LSDs are characterized by severe neurodegeneration, mental decline, and cognitive and behavioural abnormalities. Autophagy
impairment caused by defective lysosome–autophagosome coupling
triggers a pathogenic cascade by the accumulation of substrates that
contribute to neurodegenerative disorders including Parkinson’s dis -
ease, Alzheimer’s disease, Huntington’s disease and several tau-opathies.
Many lysosomal storage diseases are known, e.g. Tay–Sachs disease
(GM2 gangliosidosis), in which a faulty β-hexosaminidase A leads to
the accumulation of the glycosphingolipid GM2 ganglioside in neu -
rones, causing death during childhood. In Danon disease, a vacuolar skeletal myopathy and cardiomyopathy with neurodegeneration in
hemizygous males, lysosomes fail to fuse with autophagosomes because
of a mutation of the lysosomal membrane protein LAMP-2 (lysosomal
associated membrane protein-2).
26S proteasome
A protein can be degraded by different mechanisms, depending on
the cell type and different pathological conditions. Furthermore, the
same substrate can engage different proteolytic pathways (Park and
Cuervo 2013). Three major protein degradation mechanisms operate
in eukaryotic cells to dispose of non-functional cellular proteins:
the autophagosome–lysosomal pathway (see above); the apoptotic
procaspase–caspase pathway (see below); and the ubiquitinated
protein–26S proteasome pathway. The 26S proteasome is a multicata -
lytic protease found in the cytosol and the nucleus that degrades intra -
cellular proteins conjugated to a polyubiquitin chain by an enzymatic
cascade. The 26S proteasome consists of several subunits arranged into
two 19S polar caps, where protein recognition and adenosine 5 ′-
triphosphate (ATP)-dependent target processing occur, flanking a 20S central barrel-shaped structure with an inner proteolytic chamber
(Tomko and Hochstrasser 2013). The 26S proteasome participates in
the removal of misfolded or abnormally assembled proteins, the deg -
radation of cyclins involved in the control of the cell cycle, the process -
ing and degradation of transcription regulators, cellular-mediated
immune responses, and cell cycle arrest and apoptosis.
Peroxisomes
Peroxisomes are small (0.2–1 µm in diameter) membrane-bound
organelles present in most mammalian cells. They contain more than 50 enzymes responsible for multiple catabolic and synthetic biochemi -
cal pathways, in particular the β-oxidation of very-long-chain fatty
acids (>C22) and the metabolism of hydrogen peroxide (hence the
name peroxisome). Peroxisomes derive from the endoplasmic reticu -
lum through the transfer of proteins from the endoplasmic reticulum to peroxisomes by vesicles that bud from specialized sites of the endo -
plasmic reticulum and by a lipid non-vesicular pathway. All matrix proteins and some peroxisomal membrane proteins are synthesized by
cytosolic ribosomes and contain a peroxisome targeting signal that
enables them to be imported by proteins called peroxins (Braverman
et al 2013, Theodoulou et al 2013). Mature peroxisomes divide by
small daughter peroxisomes pinching off from a large parental peroxisome.
Peroxisomes often contain crystalline inclusions composed mainly
of high concentrations of the enzyme urate oxidase. Oxidases use
molecular oxygen to oxidize specific organic substrates (such as
L-amino
acids, D-amino acids, urate, xanthine and very-long-chain fatty acids)
and produce hydrogen peroxide that is detoxified (degraded) by per -
oxisomal catalase. Peroxisomes are particularly numerous in hepato -
cytes. Peroxisomes are important in the oxidative detoxification of various substances taken into or produced within cells, including
ethanol. Peroxin mutation is a characteristic feature of Zellweger syn -
drome (craniofacial dysmorphism and malformations of brain, liver,
eye and kidney; cerebrohepatorenal syndrome). Neonatal leukodystro -
phy is an X-linked peroxisomal disease affecting mostly males, caused by deficiency in β-oxidation of very-long-chain fatty acids. The build-up
of very-long-chain fatty acids in the nervous system and suprarenal glands determines progressive deterioration of brain function and suprarenal insufficiency (Addison’s disease). For further reading, see
Braverman et al (2013).
Fig . 1 .6 A, Mitochondria in human cardiac muscle . The folded cristae
(arrows) project into the matrix from the inner mitochondrial membrane .
B, The location of the elementary particles that couple oxidation and
phosphorylation reactions . (A, Courtesy of Dr Bart Wagner,
Histopathology Department, Sheffield Teaching Hospitals, UK .)
A
B
Elementary
particlesCristae (folds)Inner membraneOuter membrane | 39 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
9.e1
CHaPTER 1
The transcription factor EB (TFEB) is responsible for regulating lyso -
somal biogenesis and function, lysosome-to-nucleus signalling and
lipid catabolism (for further reading, see Settembre et al (2013)). If any
of the actions of lysosomal hydrolases, of the lysosome acidification
mechanism or of lysosomal membrane proteins fails, the degradation
and recycling of extracellular substrates delivered to lysosomes by the
late endosome and the degradation and recycling of intracellular sub -
strates by autophagy lead to progressive lysosomal dysfunction in several tissues and organs.
Experimentally, TFEB activation can reduce the accumulation of
the pathogenic protein in a cellular model of Huntington’s disease (a
neurodegenerative genetic disorder that affects muscle coordination)
and improves the Parkinson’s disease phenotype in a murine model.
Cristae are abundant in mitochondria seen in cardiac muscle
cells and in steroid-producing cells (in the suprarenal cortex, corpus
luteum and Leydig cells). The protein steroidogenic acute regulatory
protein (StAR) regulates the synthesis of steroids by transporting
cholesterol across the outer mitochondrial membrane. A mutation
in the gene encoding StAR causes defective suprarenal and gonadal
steroidogenesis. | 40 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
10 SECTION 1
ent and its electronic charge, and the potential difference across the
membrane. These factors combine to produce an electrochemical gradi -
ent, which governs ion flux. Channel proteins are utilized most effec -
tively by the excitable plasma membranes of nerve cells, where the
resting membrane potential can change transiently from about −80 mV
(negative inside the cell) to +40 mV (positive inside the cell) when
stimulated by a neurotransmitter (as a result of the opening and sub -
sequent closure of channels selectively permeable to sodium and potassium).
Carrier proteins bind their specific solutes, such as amino acids, and
transport them across the membrane through a series of conforma -
tional changes. This latter process is slower than ion transport through membrane channels. Transport by carrier proteins can occur either pas -
sively by simple diffusion, or actively against the electrochemical gradi -
ent of the solute. Active transport must therefore be coupled to a source
of energy, such as ATP generation, or energy released by the coordinate
movement of an ion down its electrochemical gradient. Linked trans -
port can be in the same direction as the solute, in which case the carrier protein is described as a symporter, or in the opposite direction, when
the carrier acts as an antiporter.
Translocation of proteins across
intracellular membranes
Proteins are generally synthesized on ribosomes in the cytosol or on the rough endoplasmic reticulum. A few are made on mitochondrial
ribosomes. Once synthesized, many proteins remain in the cytosol,
where they carry out their functions. Others, such as integral membrane
proteins or proteins for secretion, are translocated across intracellular
membranes for post-translational modification and targeting to their
destinations. This is achieved by the signal sequence, an addressing
system contained within the protein sequence of amino acids, which is
recognized by receptors or translocators in the appropriate membrane.
Proteins are thus sorted by their signal sequence (or set of sequences
that become spatially grouped as a signal patch when the protein folds
into its tertiary configuration), so that they are recognized by and enter
the correct intracellular membrane compartment.
Cell signalling
Cellular systems in the body communicate with each other to coordi -
nate and integrate their functions. This occurs through a variety of processes known collectively as cell signalling, in which a signalling
molecule produced by one cell is detected by another, almost always by
means of a specific receptor protein molecule. The recipient cell trans -
duces the signal, which it most often detects at the plasma membrane, into intracellular chemical messages that change cell behaviour.
The signal may act over a long distance, e.g. endocrine signalling
through the release of hormones into the blood stream, or neuronal
synaptic signalling via electrical impulse transmission along axons
and subsequent release of chemical transmitters of the signal at syn -
apses or neuromuscular junctions. A specialized variation of endocrine
signalling (neurocrine or neuroendocrine signalling) occurs when neu -
rones or paraneurones (e.g. chromaffin cells of the suprarenal medulla) secrete a hormone into interstitial fluid and the blood stream.
Alternatively, signalling may occur at short range through a paracrine
mechanism, in which cells of one type release molecules into the inter -
stitial fluid of the local environment, to be detected by nearby cells of a different type that express the specific receptor protein. Neurocrine
cell signalling uses chemical messengers found also in the central
nervous system, which may act in a paracrine manner via interstitial
fluid or reach more distant target tissues via the blood stream. Cells
may generate and respond to the same signal. This is autocrine signal -
ling, a phenomenon that reinforces the coordinated activities of a group of like cells, which respond together to a high concentration of a local
signalling molecule. The most extreme form of short-distance signalling
is contact-dependent (juxtacrine) signalling, where one cell responds to
transmembrane proteins of an adjacent cell that bind to surface recep -
tors in the responding cell membrane. Contact-dependent signalling also includes cellular responses to integrins on the cell surface binding
to elements of the extracellular matrix. Juxtacrine signalling is impor -
tant during development and in immune responses. These different
types of intercellular signalling mechanism are illustrated in Figure 1.7.
For further reading on cell signalling pathways, see Kierszenbaum and
Tres (2012).
Signalling molecules and their receptors
The majority of signalling molecules (ligands) are hydrophilic and so cannot cross the plasma membrane of a recipient cell to effect changes erythrocytes lack mitochondria altogether. Cells with few mitochondria
generally rely largely on glycolysis for their energy supplies. These
include some very active cells, e.g. fast twitch skeletal muscle fibres,
which are able to work rapidly but for only a limited duration. Mito -
chondria appear in the light microscope as long, thin structures in the cytoplasm of most cells, particularly those with a high metabolic rate,
e.g. secretory cells in exocrine glands. In living cells, mitochondria
constantly change shape and intracellular position; they multiply by
growth and fission, and may undergo fusion.
The mitochondrial matrix is an aqueous environment. It contains a
variety of enzymes, and strands of mitochondrial DNA with the capacity
for transcription and translation of a unique set of mitochondrial genes
(mitochondrial mRNAs and transfer RNAs, mitochondrial ribosomes
with rRNAs). The DNA forms a closed loop, about 5 µm across; several
identical copies are present in each mitochondrion. The ratio between its bases differs from that of nuclear DNA, and the RNA sequences also
differ in the precise genetic code used in protein synthesis. At least 13
respiratory chain enzymes of the matrix and inner membrane are
encoded by the small number of genes along the mitochondrial DNA.
The great majority of mitochondrial proteins are encoded by nuclear
genes and made in the cytosol, then inserted through special channels
in the mitochondrial membranes to reach their destinations. Their
membrane lipids are synthesized in the endoplasmic reticulum.
It has been shown that mitochondria are of maternal origin because
the mitochondria of spermatozoa are not generally incorporated
into the ovum at fertilization. Thus mitochondria (and mitochondrial genetic variations and mutations) are passed only through the
female line.
Mitochondria are distributed within a cell according to regional
energy requirements, e.g. near the bases of cilia in ciliated epithelia, in the basal domain of the cells of proximal convoluted tubules in the
renal cortex (where considerable active transport occurs) and around
the proximal segment, called middle piece, of the flagellum in sperma -
tozoa. They may be involved with tissue-specific metabolic reactions, e.g. various urea-forming enzymes are found in liver cell mitochondria.
Moreover, a number of genetic diseases of mitochondria affect particu -
lar tissues exclusively, e.g. mitochondrial myopathies (skeletal muscle) and mitochondrial neuropathies (nervous tissue). For further informa -
tion on mitochondrial genetics and disorders, see Chinnery and Hudson (2013).
Cytosolic inclusions
The aqueous cytosol surrounds the membranous organelles described
above. It also contains various non-membranous inclusions, including
free ribosomes, components of the cytoskeleton, and other inclusions,
such as storage granules (e.g. glycogen), pigments (such as lipofuscin
granules, remnants of the lipid oxidative mechanism seen in the supra -
renal cortex) and lipid droplets.
lipid droplets
Lipid droplets are spherical bodies of various sizes found within many
cells, but are especially prominent in the adipocytes (fat cells) of
adipose connective tissue. They do not belong to the Golgi-related vacu -
olar system of the cell. They are not membrane-bound, but are droplets of lipid suspended in the cytosol and surrounded by perilipin proteins,
which regulate lipid storage and lipolysis. See Smith and Ordovás
(2012) for further reading on obesity and perilipins. In cells specialized
for lipid storage, the vacuoles reach 80 µm or more in diameter. They
function as stores of chemical energy, thermal insulators and mechani -
cal shock absorbers in adipocytes. In many cells, they may represent end-products of other metabolic pathways, e.g. in steroid-synthesizing
cells, where they are a prominent feature of the cytoplasm. They may
also be secreted, as in the alveolar epithelium of the lactating breast.
Transport across cell membranes
Lipid bilayers are increasingly impermeable to molecules as they increase in size or hydrophobicity. Transport mechanisms are therefore
required to carry essential polar molecules, including ions, nutrients,
nucleotides and metabolites of various kinds, across the plasma mem -
brane and into or out of membrane-bound intracellular compartments. Transport is facilitated by a variety of membrane transport proteins,
each with specificity for a particular class of molecule, e.g. sugars. Trans -
port proteins fall mainly into two major classes: channel proteins and
carrier proteins.
Channel proteins form aqueous pores in the membrane, which open
and close under the regulation of intracellular signals, e.g. G-proteins, to allow the flux of solutes (usually inorganic ions) of specific size and charge. Transport through ion channels is always passive, and ion flow through an open channel depends only on the ion concentration gradi - | 41 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
10.e1
CHaPTER 1
Mitochondrial ribosomes are smaller and quite distinct from those
of the rest of the cell in that they (and mitochondrial nucleic acids)
resemble those of bacteria. This similarity underpins the theory that mitochondrial ancestors were oxygen-utilizing bacteria that existed in a symbiotic relationship with eukaryotic cells unable to metabolize the
oxygen produced by early plants. As mitochondria are formed only
from previously existing ones, it follows that all mitochondria in the body are descended from those in the cytoplasm of the fertilized ovum. | 42 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
11
CHaPTER 1
among signalling molecules in having no specific receptor protein; it
acts directly on intracellular enzymes of the response pathway.
Receptor proteins
There are some 20 different families of receptor proteins, each with several isoforms responding to different ligands. The great majority of these receptors are transmembrane proteins. Members of each family
share structural features that indicate either shared ligand-binding char -
acteristics in the extracellular domain or shared signal transduction properties in the cytoplasmic domain, or both. There is little relation -
ship either between the nature of a ligand and the family of receptor proteins to which it binds and activates, or the signal transduction
strategies by which an intracellular response is achieved. The same
ligand may activate fundamentally different types of receptor in differ -
ent cell types.
Cell surface receptor proteins are generally grouped according to
their linkage to one of three intracellular systems: ion channel-linked receptors; G-protein coupled receptors; and receptors that link to
enzyme systems. Other receptors do not fit neatly into any of these
categories. All the known G-protein coupled receptors belong to a
structural group of proteins that pass through the membrane seven
times in a series of serpentine loops. These receptors are thus known as
seven-pass transmembrane receptors or, because the transmembrane
regions are formed from α-helical domains, as seven-helix receptors.
The best known of this large group of phylogenetically ancient receptors are the odorant-binding proteins of the olfactory system; the light-
sensitive receptor protein, rhodopsin; and many of the receptors for
clinically useful drugs. A comprehensive list of receptor proteins, their
activating ligands and examples of the resultant biological function is
given in Pollard and Earnshaw (2008).
Intracellular signalling
A wide variety of small molecules carry signals within cells, conveying
the signal from its source (e.g. activated plasma membrane receptor) to its target (e.g. the nucleus). These second messengers convey signals as fluctuations in local concentration, according to rates of synthesis and degradation by specific enzymes (e.g. cyclases involved in cyclic nucle -
otide (cAMP, cGMP) synthesis), or, in the case of calcium, according to the activities of calcium channels and pumps. Other, lipidic, second inside the cell unless they first bind to a plasma membrane receptor
protein. Ligands are mainly proteins (usually glycoproteins), polypep -
tides or highly charged biogenic amines. They include: classic peptide hormones of the endocrine system; cytokines, which are mainly of
haemopoietic cell origin and involved in inflammatory responses and
tissue remodelling (e.g. the interferons, interleukins, tumour necrosis
factor, leukaemia inhibitory factor); and polypeptide growth factors (e.g. the epidermal growth factor superfamily, nerve growth factor,
platelet-derived growth factor, the fibroblast growth factor family, trans -
forming growth factor beta and the insulin-like growth factors). Polypeptide growth factors are multifunctional molecules with more
widespread actions and cellular sources than their names suggest. They
and their receptors are commonly mutated or aberrantly expressed in
certain cancers. The cancer-causing gene variant is termed a transform -
ing oncogene and the normal (wild-type) version of the gene is a cel -
lular oncogene or proto-oncogene. The activated receptor acts as a
transducer to generate intracellular signals, which are either small dif-
fusible second messengers (e.g. calcium, cyclic adenosine monophos -
phate or the plasma membrane lipid-soluble diacylglycerol), or larger protein complexes that amplify and relay the signal to target control
systems.
Some signals are hydrophobic and able to cross the plasma mem -
brane freely. Classic examples are the steroid hormones, thyroid hor -
mones, retinoids and vitamin D. Steroids, for instance, enter cells non-selectively, but elicit a specific response only in those target cells
that express specific cytoplasmic or nuclear receptors. Light stimuli also
cross the plasma membranes of photoreceptor cells and interact intra -
cellularly, at least in rod cells, with membrane-bound photosensitive receptor proteins. Hydrophobic ligands are transported in the blood
stream or interstitial fluids, generally bound to carrier proteins, and they
often have a longer half-life and longer-lasting effects on their targets
than do water-soluble ligands.
A separate group of signalling molecules able to cross the plasma
membrane freely is typified by the gas, nitric oxide. The principal target of short-range nitric oxide signalling is smooth muscle, which relaxes in response. Nitric oxide is released from vascular endothelium as a result of the action of autonomic nerves that supply the vessel wall causing local relaxation of smooth muscle and dilation of vessels. This mechanism is responsible for penile erection. Nitric oxide is unusual Fig . 1 .7 The different modes of cell–cell signalling .
A Endocrine B Paracrine
C Autocrine D Synaptic
E Neurocrine F Contact-dependentEndocrine cell A
Different
hormonesTarget cell BReceptor Y
Target cell ABlood streamEndocrine cell B
Receptor X
Target
cellsSignalling
cell
Membrane receptor
Hormone or
growth factorTarget cellSynapse
Neurotransmitter Cell bodyAxonNeurone
Distant target cellNeuroendocrinecellStimulus
Blood vessel
Membrane-bound
signal moleculeSignalling cell Target cellShort-range signalling
molecule
Neuropeptide
or amine | 43 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
12 SECTION 1
are microfilaments (7 nm thick), microtubules (25 nm thick) and inter -
mediate filaments (10 nm thick). Other important components are
proteins that bind to the principal filamentous types to assemble or
disassemble them, regulate their stability or generate movement. These
include actin-binding proteins such as myosin, which in some cells can
assemble into thick filaments, and microtubule-associated proteins.
Pathologies involving cytoskeletal abnormalities include ciliopathies
(resulting from the abnormal assembly and function of centrioles, basal
bodies and cilia); neurodegenerative diseases (a consequence of defec-
tive anterograde transport of neurotransmitters along microtubules in
axons); and sterility (determined by defective or absent microtubule-
associated dynein in axonemes, e.g. Kartagener’s syndrome).
Actin filaments (microfilaments)
Actin filaments are flexible filaments, 7 nm thick ( Fig. 1.8). Within
most cell types, actin constitutes the most abundant protein and in
some motile cells its concentration may exceed 200 µM (10 mg protein
per ml cytoplasm). The filaments are formed by the ATP-dependent
polymerization of actin monomer (with a molecular mass of 43 kDa)
into a characteristic string of beads in which the subunits are arranged in a linear tight helix with a distance of 13 subunits between turns
(Dominguez 2010). The polymerized filamentous form is termed
F-actin (fibrillar actin) and the unpolymerized monomeric form is
known as G-actin (globular actin). Each monomer has an asymmetric
structure. When monomers polymerize, they confer a defined polarity
on the filament: the plus or barbed end favours monomer addition,
and the minus or pointed end favours monomer dissociation.
Treadmilling designates the simultaneous polymerization of an
actin filament at one end and depolymerization at the other end to
maintain its constant length.
See Bray (2001) for further reading.
actin-binding proteins
A wide variety of actin-binding proteins are capable of modulating the
form of actin within the cell. These interactions are fundamental to the
messengers such as phosphatidylinositol, derive from membranes and may act within the membrane to generate downstream effects. For
further consideration of the complexity of intracellular signalling path-
ways, see Pollard and Earnshaw (2008).
Cytoskeleton
The cytoskeleton is a three-dimensional network of filamentous intra -
cellular proteins of different shapes, sizes and composition distributed throughout the cytoplasm. It provides mechanical support, maintains
cell shape and rigidity, and enables cells to adopt highly asymmetric or
irregular profiles. It plays an important part in establishing structural
polarity and different functional domains within a cell. It also provides
mechanical support for permanent projections from the cell surface (see
below), including persistent microvilli and cilia, and transient proc -
esses, such as the thin finger-like protrusions called filopodia (0.1–
0.3 µm) and lamellipodia (0.1–0.2 µm). Filopodia consist of parallel
bundles of actin filaments and have a role in cell migration, wound
healing and neurite growth. The protrusive thin and broad lamellipo -
dia, found at the leading edge of a motile cell, contain a branched network of actin filaments.
The cytoskeleton restricts specific structures to particular cellular
locations. For example, the Golgi apparatus is near the nucleus and
endoplasmic reticulum, and mitochondria are near sites of energy
requirement. In addition, the cytoskeleton provides tracks for intracel-
lular transport (e.g. shuttling vesicles and macromolecules, called
cargoes, among cytoplasmic sites), the movement of chromosomes
during cell division (mitosis and meiosis) or movement of the entire
cell during embryonic morphogenesis or the chemotactic extravascular
migration of leukocytes during homing. Examples of highly developed
and specialized functions of the cytoskeleton include the contraction
of the sarcomere in striated muscle cells and the bending of the axoneme
of cilia and flagella.
The catalogue of cytoskeletal structural proteins is extensive and still
increasing. The major filamentous structures found in non-muscle cells
Fig . 1 .8 Structural and molecular
features of cytoskeletal components .
A, The actin filament (F-actin) is a
7 nm thick polymer chain of
ATP-bound G-actin monomers .
F-actin consists of a barbed (plus)
end, the initiation site of F-actin,
and a pointed (minus) end, the
dissociation site of F-actin . F-actin
can be severed and capped at the
barbed end by gelsolin . B, The
microtubule is a 25 nm diameter
polymer of GTP-bound α-tubulin and
GTP-bound β-tubulin dimers . The
dimer assembles at the plus end and
depolymerizes at the minus end . A
linear chain of α-tubulin/β-tubulin
dimers is called a protofilament . In
the end-on (top view), a microtubule displays 13 concentrically arranged
tubulin subunits . C, Tetrameric
complexes of intermediate filament
subunits associate laterally to form a
unit length filament consisting of
eight tetramers . Additional unit length
filaments anneal longitudinally and
generate a mature 10 nm thick
intermediate filament . Tetramer
Unit length filament
Intermediate filament
Intermediate filament Microtubule Actin filament C B A10 nm thick25 nm in diameter 7 nm thick
Top view:
13 concentric tubulinsProtofilamentMinus end Severed actin filament
Capped barbed endGelsolin
Pointed endPlus end
Barbed endTubulin dimer Monomer
GTPGTP
GTPG-actin–ATPβ-tubulin
α-tubulin | 44 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
12.e1
CHaPTER 1
Septins are emerging as a novel cytoskeletal member because of their
filamentous organization and association with actin filaments and
microtubules. They are guanosine triphosphate (GTP)-binding proteins
that form hetero-oligomeric complexes (see Mostowy and Cossart
(2012) for additional information).
This polarity can be visualized in negatively stained images by allow-
ing F-actin to react with fragments containing the active head region of myosin. Myosins bind to filamentous actin at an angle to give the
appearance of a series of arrowheads pointing towards the minus end
of the filament, with the barbs pointing towards the plus end.
It involves the addition of ATP-bound G-actin monomers at the
barbed end (fast-growing plus end) and removal of ADP-bound G-actin
at the pointed end (slow-growing minus end). Actin filaments grow or
shrink by addition or loss of G-actin monomer at both ends. Essentially,
actin polymerization in vitro proceeds in three steps: nucleation (aggre -
gation of G-actin monomers into a 3–4-monomer aggregate), elonga -
tion (addition of G-actin monomers to the aggregate) and a dynamic
steady state (treadmilling). Specific toxins (e.g. cytochalasins, phalloi -
dins and lantrunculins) bind to actin and affect its polymerization. Cytochalasin D blocks the addition of new G-actin monomers to the
barbed end of F-actin; phalloidin binds to the interface between G-actin
monomers in F-actin, thus preventing depolymerization; and lantrun-
culin binds to G-actin monomers, blocking their addition to an actin
filament. | 45 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
13
CHaPTER 1
organization of cytoplasm and to cell shape. The actin cytoskeleton is
organized as closely packed parallel arrays of actin filaments forming
bundles or cables, or loosely packed criss-crossed actin filaments
forming networks (Fig. 1.9A). Actin-binding proteins hold together
bundles and networks of actin filaments. Actin-binding proteins can
be grouped into G-actin (monomer) binding proteins and F-actin (polymer) capping, cross-linking and severing proteins. Actin-binding
proteins may have more than one function.
Capping proteins bind to the ends of the actin filament either
to stabilize an actin filament or to promote its disassembly (see
Fig. 1.8).
Cross-linking or bundling proteins tie actin filaments together in
longitudinal arrays to form bundles, cables or core structures. The bundles may be closely packed in microvilli and filopodia, where paral -
lel filaments are tied tightly together to form stiff bundles orientated in
the same direction. Cross-linking proteins of the microvillus actin bundle core include fimbrin and villin.
Other actin-bundling proteins form rather looser bundles of fila -
ments that run antiparallel to each other with respect to their plus and minus ends. They include myosin II, which can form cross-links with ATP-dependent motor activity, and cause adjacent actin filaments to slide on each other in the striated muscle sarcomere, and either change the shape of cells or (if the actin bundles are anchored into the cell Fig . 1 .9 The
cytoskeleton . A, An
immunofluorescence
micrograph of α-actin
microfilaments (green) in human airway smooth
muscle cells in culture .
The actin-binding
protein, vinculin (red), is
localized at the ends of
actin filament bundles;
nuclei are blue . B, An
immunofluorescence
micrograph of keratin
intermediate filaments
(green) in human
keratinocytes in culture .
Desmosome junctions
are labelled with
antibody against
desmoplakin (red) .
Nuclei are stained blue
(Hoechst) . C, An
electron micrograph of human nerve showing
microtubules (small,
hollow structures in
cross-section, long
arrow) in a transverse
section of an
unmyelinated axon (A),
engulfed by a Schwann
cell (S) . Neuronal
intermediate filaments (neurofilaments) are the
solid, electron-dense
profiles, also in
transverse section (short
arrow) . (A, Courtesy of
Dr T Nguyen, Professor
J Ward, Dr SJ Hirst,
King’s College London .
B, Courtesy of Prof .
Dr WW Franke, German
Cancer Research
Centre, Heidelberg .
C, Courtesy of Dr Bart Wagner, Histopathology
Department, Sheffield
Teaching Hospitals, UK .)
A
B
CSA
SAmembrane at both ends), maintain a degree of active rigidity. Filamin
interconnects adjacent actin filaments to produce loose filamentous
gel-like networks composed of randomly orientated F-actin.
F-actin can branch. The assembly of branched filamentous actin
networks involves a complex of seven actin-related proteins 2/3
(Arp2/3) that is structurally similar to the barbed end of actin.
See Rotty et al (2013) for further reading.
Branched actin generated by the Arp2/3 protein complex localizes
at the leading edge of migrating cells, lamellipodia and phagosomes
(required for the capture by endocytosis and phagocytosis of particles
and foreign pathogens by immune cells). Formin can elongate pre-
existing actin filaments by removing capping proteins at the barbed
end.
Other classes of actin-binding protein link the actin cytoskeleton to
the plasma membrane either directly or indirectly through a variety of
membrane-associated proteins. The latter may also create links via
transmembrane proteins to the extracellular matrix. Best known of
these is the family of spectrin-like molecules, which can bind to actin
and also to each other and to various membrane-associated proteins to
create supportive networks beneath the plasma membrane. Tetrameres
of spectrin α and β chains line the intracellular side of the plasma
membrane of erythrocytes and maintain their integrity by their associa -
tion with short actin filaments at either end of the tetramer.
Class V myosins are unconventional motor proteins transporting
cargoes (such as vesicles and organelles) along actin filaments.
Class I myosins are involved in membrane dynamics and actin organi -
zation at the cell cortex, thus affecting cell migration, endocytosis,
pinocytosis and phagocytosis. Tropomyosin, an important regulatory
protein of muscle fibres, is also present in non-muscle cells, where
its function may be primarily to stabilize actin filaments against depolymerization.
Myosins, the motor proteins
The myosin family of microfilaments is often classified within a distinct category of motor proteins. Myosin proteins have a globular head
region consisting of a heavy and a light chain. The heavy chain bears
an α-helical tail of varying length. The head has an ATPase activity and
can bind to and move along actin filaments – the basis for myosin function as a motor protein. The best-known class is myosin II, which
occurs in muscle and in many non-muscle cells. Its molecules have two
heads and two tails, intertwined to form a long rod. The rods can bind
to each other to form long, thick filaments, as seen in striated and
smooth muscle fibres and myoepithelial cells. Myosin II molecules can
also assemble into smaller groups, especially dimers, which can cross-
link individual actin microfilaments in stress fibres and other F-actin
arrays. The ATP-dependent sliding of myosin on actin forms the basis
for muscle contraction and the extension of microfilament bundles, as
seen in cellular motility or in the contraction of the ring of actin and
myosin around the cleavage furrow of dividing cells. There are a number
of known subtypes of myosin II; they assemble in different ways and
have different dynamic properties. In skeletal muscle the myosin mol -
ecules form bipolar filaments 15 nm thick. Because these filaments have
a symmetric antiparallel arrangement of subunits, the midpoint is bare of head regions. In smooth muscle the molecules form thicker, flattened
bundles and are orientated in random directions on either face of the
bundle. These arrangements have important consequences for the con -
tractile force characteristics of the different types of muscle cell.
Related molecules include the myosin I subfamily of single-headed
molecules with tails of varying length. Functions of myosin I include the movements of membranes in endocytosis, filopodial formation in
neuronal growth cones, actin–actin sliding and attachment of actin to
membranes as seen in microvilli. As indicated above, molecular motors
of the myosin V family are implicated in the movements of cargoes on
actin filaments. So, for example, myosin Va transports vesicles along
F-actin tracks in a similar manner to kinesin and cytoplasmic dynein-
related cargo transport along microtubules. Each class of motor protein
has different properties, but during cargo trafficking they often function
together in a coordinated fashion. (See Hammer 3rd and Sellers (2012)
for further reading on class V myosins.)
Other thin filaments
A heterogeneous group of filamentous structures with diameters of
2–4 nm occurs in various cells. The two most widely studied forms, titin
and nebulin, constitute around 13% of the total protein of skeletal
muscle. They are amongst the largest known molecules and have subunit weights of around 10
6; native molecules are about 1 µm in
length. Their repetitive bead-like structure gives them elastic properties that are important for the effective functioning of muscle, and possibly for other cells. | 46 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
13.e1
CHaPTER 1
Profilin and thymosin β4 are G-actin binding proteins. Profilin binds
to G-actin bound to ATP; it inhibits addition of G-actin to the slow-
growing (pointed) end of F-actin but enables the fast-growing (barbed) end to grow faster and then dissociates from the actin filament. In addi -
tion, profilin participates in the conversion of ADP back to the ATP–G-
actin bound form. Thymosin β4 binds to the ATP–G-actin bound form,
preventing polymerization by sequestering ATP–G-actin into a reserve
pool.
Members of the F-actin capping protein family are heterodimers
consisting of an α subunit (CP α) and a β subunit (CP β) that cap the
barbed end of actin filaments within all eukaryotic cells. Gelsolin has a dual role: it severs F-actin and caps the newly formed barbed end, blocking further filament elongation.
Fascin is an additional cross-linking protein. Villin is also a severing
protein, causing the disassembly of actin filaments and the collapse of the microvillus.In the presence of activated nucleation promotion factors, such as
Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE, also known as SCAR), the Arp2/3 protein complex binds to the side of an existing actin filament (mother fila -
ment) and initiates the formation of a branching actin daughter fila -
ment at a 70° angle relative to the mother filament utilizing G-actin delivered to the Arp2/3 complex site.
Spectrin-related molecules are present in many other cells. For
instance, fodrin is found in neurones and dystrophin occurs in muscle cells, linking the contractile apparatus with the extracellular matrix via integral membrane proteins. Proteins such as ankyrin (which also binds
actin directly), vinculin, talin, zyxin and paxillin connect actin-binding
proteins to integral plasma membrane proteins such as integrins
(directly or indirectly), and thence to focal adhesions (consisting of a
bundle of actin filaments attached to a portion of a plasma membrane
linked to the extracellular matrix). | 47 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
14 SECTION 1
microtubules for considerable distances, thus enabling selective target -
ing of materials within the cell. Such movements occur in both direc -
tions along microtubules. Kinesin-dependent motion is usually towards
the plus ends of microtubules, e.g. from the cell body towards the axon
terminals in neurones, and away from the centrosome in other cells.
Conversely, dynein-related movements are in the opposite direction, i.e.
to the minus ends of microtubules. Dyneins also form the arms of
peripheral microtubules in cilia and flagella, where they make dynamic
cross-bridges to adjacent microtubule pairs. When these tethered
dyneins try to move, the resulting shearing forces cause the axonemal
array of microtubules to bend, generating ciliary and flagellar beating
movements. Kinesins form a large and diverse family of related
microtubule-stimulated ATPases. Some kinesins are motors that move
cargo and others cause microtubule disassembly, whilst still others
cross-link mitotic spindle microtubules to push the two centriolar poles
apart during mitotic prophase. See Bray (2001) for further reading.
Centrioles, centrosomes and basal bodies
Centrioles are microtubular cylinders 0.2 µm in diameter and 0.4 µm
long (Fig. 1.10). They are formed by a ring of nine microtubule triplets linked by a number of other proteins. At least two centrioles occur in
all animal cells that are capable of mitotic division (eggs, which undergo
meiosis instead of mitosis, lack centrioles). See Gönczy (2012) for
further reading on the structure and assembly of the centriole. They usually lie close together, at right angles or, most usually, at an oblique
angle to each other (an arrangement often termed a diplosome), within
the centrosome, a densely filamentous region of cytoplasm at the centre
of the cell. The centrosome is the major microtubule-organizing centre
of most cells; it is the site at which new microtubules are formed and
the mitotic spindle is generated during cell division. Centriole biogen -
esis is a complex process. At the beginning of the S phase (DNA replica -
tion phase) of the cell cycle (see below), a new daughter centriole forms
at right angles to each separated maternal centriole. Each mother–
daughter pair forms one pole of the next mitotic spindle, and the
daughter centriole becomes fully mature only as the progeny cells are
about to enter the next mitosis. Because centrosomes are microtubule-
organizing centres, they lie at the centre of a network of microtubules,
all of which have their minus ends proximal to the centrosome.
The microtubule-organizing centre contains complexes of γ-tubulin
that nucleate microtubule polymerization at the minus ends of micro-
tubules. Basal bodies are microtubule-organizing centres that are closely
related to centrioles, and are believed to be derived from them. They
are located at the bases of cilia and flagella, which they anchor to the
cell surface. The outer microtubule doublets of the axoneme of cilia and
flagella originate from two of the microtubules in each triplet of the basal body.
microtubule-based transport of cargoes
The transport of cargoes along microtubules via the motor proteins kinesin and cytoplasmic dynein respectively is the means by which neurotransmitters are delivered along axons to neuronal synapses
Microtubules
Microtubules are polymers of tubulin with the form of hollow, rela-
tively rigid cylinders, approximately 25 nm in diameter and of varying
length (up to 70 µm in spermatozoan flagella). They are present in most
cell types, being particularly abundant in neurones, leukocytes and
blood platelets. Microtubules are the predominant constituents of the
mitotic spindles of dividing cells and also form part of the axoneme of
cilia, flagella and centrioles.
Microtubules consist of tubulin dimers and microtubule-associated
proteins. There are two major classes of tubulin: α- and β-tubulins.
Before microtubule assembly, tubulins are associated as dimers with a
combined molecular mass of 100 kDa (50 kDa each). Each protein
subunit is approximately 5 nm across and is arranged along the long
axis in straight rows of alternating α- and β-tubulins, forming protofila-
ments (see Fig. 1.8). Typically, 13 protofilaments (the number can vary
between 1 1 and 16) associate in a ring to form the wall of a hollow
cylindrical microtubule. Each longitudinal row is slightly out of align -
ment with its neighbour, so that a spiral pattern of alternating α and β
subunits appears when the microtubule is viewed from the side. There
is a dynamic equilibrium between the dimers and assembled microtu -
bules: dimeric asymmetry creates polarity ( α-tubulins are all orientated
towards the minus end, β-tubulins towards the plus end). Tubulin is
added preferentially to the plus end; the minus end is relatively slow-growing. Microtubules frequently grow and shrink at a rapid and con -
stant rate, a phenomenon known as dynamic instability, in which growing tubules can undergo a ‘catastrophe’, abruptly shifting from net
growth to rapid shrinkage. The primary determinant of whether micro -
tubules grow or shrink is the rate of GTP hydrolysis. Tubulins are GTP-binding proteins; microtubule growth is accompanied by hydrolysis of
GTP, which may regulate the dynamic behaviour of the tubules. Micro -
tubule growth is initiated at specific sites, the microtubule-organizing centres, of which the best known are centrosomes (from which most
cellular microtubules polymerize) and the centriole-derived basal
bodies (from which cilia grow). Microtubule-organizing centres include
a specialized tubulin isoform known as γ-tubulin that is essential for
the nucleation of microtubule growth.
Various drugs (e.g. colcemid, vinblastine, griseofulvin, nocodazole)
cause microtubule depolymerization by binding the soluble tubulin dimers and so shifting the equilibrium towards the unpolymerized
state. Microtubule disassembly causes a wide variety of effects, including
the inhibition of cell division by disruption of the mitotic spindle.
Conversely, the drug paclitaxel (taxol) is a microtubule depolymeriza -
tion inhibitor because it stabilizes microtubules and promotes abnor -
mal microtubule assembly. Although this can cause a peripheral
neuropathy, paclitaxel is widely used as an effective chemotherapeutic
agent in the treatment of breast and ovarian cancer.
microtubule-associated proteins
Various proteins that can bind to assembled tubulins may be concerned
with structural properties or associated with motility. One important
class of microtubule-associated proteins (MAPs) consists of proteins
that associate with the plus ends of microtubules. They regulate the
dynamic instability of microtubules as well as interactions with other
cellular substructures. Structural MAPs form cross-bridges between adja -
cent microtubules or between microtubules and other structures such as intermediate filaments, mitochondria and the plasma membrane.
Microtubule-associated proteins found in neurones include: MAPs 1A
and 1B, which are present in neuronal dendrites and axons; MAPs 2A
and 2B, found chiefly in dendrites; and tau, found only in axons. MAP
4 is the major microtubule-associated protein in many other cell types.
Structural microtubule-associated proteins are implicated in microtu -
bule formation, maintenance and disassembly, and are therefore of considerable significance in cell morphogenesis, mitotic division, and
the maintenance and modulation of cell shape. Transport-associated
microtubule-associated proteins are found in situations in which move -
ment occurs over the surfaces of microtubules, e.g. cargo transport, bending of cilia and flagella, and some movements of mitotic spindles.
They include a large family of motor proteins, the best known of which
are the dyneins and kinesins. Another protein, dynamin, is involved in
endocytosis. The kinetochore proteins assemble at the chromosomal
centromere during mitosis and meiosis. They attach (and thus fasten
chromosomes) to spindle microtubules; some of the kinetochore pro -
teins are responsible for chromosomal movements in mitotic and meiotic anaphase.
All of these microtubule-associated proteins bind to microtubules
and either actively slide along their surfaces or promote microtubule assembly or disassembly. Kinesins and dyneins can simultaneously attach to membranes such as transport vesicles and convey them along Fig . 1 .10 A duplicated
pair of centrioles in a
human carcinoma
specimen . Each
centriole pair consists of a mother and
daughter, orientated
approximately at right
angles to each other so
that one is sectioned
transversely (T) and the
other longitudinally (L) .
The transversely
sectioned centrioles
are seen as rings of microtubule triplets
(arrow) . (Courtesy of
Dr Bart Wagner,
Histopathology
Department, Sheffield
Teaching Hospitals,
UK .)
T
LT | 48 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
14.e1
CHaPTER 1
The association of membrane vesicles with dynein motors means
that certain cytomembranes (including the Golgi apparatus) concen-
trate near the centrosome. This is convenient because the microtubules provide a means of targeting Golgi vesicular products to different parts of the cell. | 49 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
15
CHaPTER 1
sion. Of the different classes of intermediate filaments, keratin (cyto -
keratin) proteins are found in epithelia, where keratin filaments are
always composed of equal ratios of type I (acidic) and type II (basic to
neutral) keratins to form heteropolymers. About 20 types of each of the
acidic and basic/neutral keratin proteins are known. For further reading
on keratins in normal and diseased epithelia, see Pan et al (2012).
Within the epidermis, expression of keratin heteropolymers changes as keratinocytes mature during their transition from basal to superficial
layers. Genetic abnormalities of keratins are known to affect the
mechanical stability of epithelia. For example, the disease epidermolysis
bullosa simplex is caused by lysis of epidermal basal cells and blistering
of the skin after mechanical trauma. Defects in genes encoding keratins
5 and 14 produce cytoskeletal instability leading to cellular fragility in
the basal cells of the epidermis. When keratins 1 and 10 are affected,
cells in the spinous (prickle) cell layer of the epidermis lyse, and this
produces the intraepidermal blistering of epidermolytic hyperkeratosis.
See Porter and Lane (2003) for further reading.
Type III intermediate filament proteins, including vimentin, desmin,
glial fibrillary acidic protein and peripherin, form homopolymer inter -
mediate filaments. Vimentin is expressed in mesenchyme-derived cells of connective tissue and some ectodermal cells during early develop -
ment; desmins in muscle cells; glial fibrillary acidic protein in glial cells; and peripherin in peripheral axons. Type IV intermediate fila -
ments include neurofilaments, nestin, syncoilin and α-internexin. Neu-
rofilaments are a major cytoskeletal element in neurones, particularly
in axons (see Fig. 1.9C), where they are the dominant protein. Neuro -
filaments (NF) are heteropolymers of low (NF–L), medium (NF–M) and high (NF–H) molecular weight (the NF–L form is always present
in combination with either NF–M or NF–H forms). Abnormal accumu -
lations of neurofilaments (neurofibrillary tangles) are characteristic features of a number of neuropathological conditions. Nestin resem -
bles a neurofilament protein, which forms intermediate filaments in neurectodermal stem cells in particular. The type V intermediate fila -
ment group includes the nuclear lamins A, lamin B1 and lamin B2 lining the inner surface of the nuclear envelope of all nucleated cells.
Lamin C is a splice variant of lamin A. Lamins provide a mechanical
framework for the nucleus and act as attachment sites for a number of
proteins that organize chromatin at the periphery of the nucleus. They
are unusual in that they form an irregular anastomosing network of
filaments rather than linear bundles. See Burke and Stewart (2013) for
further reading.
Nucleus
The nucleus (see Figs 1.1–1.2) is generally the largest intracellular struc -
ture and is usually spherical or ellipsoid in shape, with a diameter of
3–10 µm. Conventional histological stains, such as haematoxylin or
toluidine blue, detect the acidic components (phosphate groups) of
deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in cells and
tissue sections. DNA and RNA molecules are said to be basophilic
because of the binding affinity of their negatively charged phosphate
groups to basic dyes such as haematoxylin. A specific stain for DNA is
the Feulgen reaction.
Nuclear envelope
The nucleus is surrounded by the nuclear envelope, which consists of
an inner nuclear membrane (INM) and an outer nuclear membrane
(ONM), separated by a 40–50 nm perinuclear space that is spanned by
nuclear pore complexes (NPCs). The perinuclear space is continuous with the lumen of the endoplasmic reticulum. The ONM has multiple
connections with the endoplasmic reticulum, with which it shares its
membrane protein components. The INM contains its own specific
integral membrane proteins (lamin B receptor and emerin, both pro -
viding binding sites for chromatin bridging proteins). A mutation in the gene encoding emerin causes X-linked Emery–Dreifuss muscular
dystrophy (EDMD), characterized by skeletal muscle wasting and
cardiomyopathy.
The nuclear lamina, a 15–20 nm thick, protein-dense meshwork, is
associated with the inner face of the INM. The major components of the nuclear lamina are lamins, the type V intermediate filament proteins
consisting of A-type and B-type classes.
The nuclear lamina reinforces the nuclear membrane mechanically,
determines the shape of the nucleus and provides a binding site for a
range of proteins that anchor chromatin to the cytoskeleton. Nuclear lamin A, with over 350 mutations, is the most mutated protein linked to human disease. These are referred to as laminopathies, characterized by nuclear structural abnormalities that cause structurally weakened nuclei, leading to mechanical damage. Lamin A mutations cause a
(anterograde axonal transport) and membrane-bound vesicles are
returned for recycling to the neuronal soma (retrograde axonal trans -
port) (p. 45). In addition to anterograde and retrograde motor proteins,
the assembly and maintenance of all cilia and flagella involve the par -
ticipation of non-membrane-bound macromolecular protein com -
plexes called intraflagellar transport (IFT) particles. IFT particles localize
along the polarized microtubules of the axoneme, beneath the ciliary
and flagellar membrane. IFT particles consist of two protein subcom -
plexes: IFT-A (with a role in returning cargoes from the tip of the axoneme to the cell body) and IFT-B (with a role in delivering cargoes
from the cell body to the tip of the axoneme). For further reading, see
Scholey (2008) and Hao and Scholey (2009).
During ciliogenesis, IFT requires the anterograde kinesin-2 motor
and the retrograde IFT-dynein motor to transport IFT particles–cargo
complexes in opposite directions along the microtubules, from the
basal body to the tip of the ciliary axoneme and back again (intraciliary
transport). IFT is not just restricted to microtubules of cilia and flagella.
During spermatid development, IFT particles–motor protein–cargo
complexes appear to utilize microtubules of the manchette, a transient
microtubule-containing structure, to deliver tubulin dimers and other
proteins by intramanchette transport during the development of the
spermatid tail (Kierszenbaum et al 201 1). IFT also occurs along the
modified cilium of photoreceptor cells of the retina. Mutations in IFT proteins lead to the absence of cilia and are lethal during embryogen-
esis. Ciliopathies, many related to the defective sensory and/or mechan -
ical function of cilia, include retinal degeneration, polycystic kidney disease, Bardet–Biedl syndrome, Jeune asphyxiating thoracic dystrophy,
respiratory disease and defective determination of the left–right axis.
The seven-protein complex designated BBSome (for Bardet–Biedl syn-
drome, an obesity/retinopathy ciliopathy) is a component of the basal
body and participates in the formation of the primary cilium by regulat -
ing the export and/or import of ciliary proteins. The transport of the BBSome up and down and round about in cilia occurs in association
with anterograde IFT-B and retrograde IFT-A particles. For further
reading on the BBSome, see Jin and Nachury (2009). For further reading
on ciliogenesis, see Baldari and Rosenbaum (2010).
Intermediate filaments
Intermediate filaments are about 10 nm thick and are formed by a
heterogeneous group of filamentous proteins. In contrast to actin fila -
ments and microtubules, which are assembled from globular proteins with nucleotide-binding and hydrolysing activity, intermediate fila -
ments consist of filamentous monomers lacking enzymatic activity. Intermediate filament proteins assemble to form linear filaments in a
three-step process. First, a pair of intermediate filament protein sub -
units, each consisting of a central α-helical rod domain of about 310
amino acids flanked by head and tail non- α-helical domains of varia-
ble size, form a parallel dimer through their central α-helical rod
domains coiled around each other. The variability of intermediate fila -
ment protein subunits resides in the length and amino-acid sequence
of the head and tail domains, thought to be involved in regulating the
interaction of intermediate filaments with other proteins. Second, a
tetrameric unit is formed by two antiparallel half-staggered coiled
dimers. Third, eight tetramers associate laterally to form a 16 nm thick
unit length filament (ULF). Individual ULFs join end to end to form short filaments that continue growing longitudinally by annealing to
other ULFs and existing filaments. Filament elongation is followed by
internal compaction leading to the 30 nm thick intermediate filament
(see Fig. 1.8). The tight association of dimers, tetramers and ULFs pro -
vides intermediate filaments with high tensile strength and resistance to stretching, compression, twisting and bending forces. In contrast to
actin filaments and microtubules, intermediate filaments are non-
polar (because of the antiparallel alignment of the initial tetramers)
and do not bind nucleo tides (as in G-actin and tubulin dimers), and
ULFs anneal end to end to each other (in contrast to the polarized
F-actin and microtubules, with one end, the plus end, growing faster
than the other end, the minus end). See Herrmann et al (2007) for
further reading.
Intermediate filaments are found in different cell types and are often
present in large numbers, either to provide structural strength where it is needed (see Fig. 1.9B,C) or to provide scaffolding for the attachment
of other structures. Intermediate filaments form extensive cytoplasmic
networks extending from cage-like perinuclear arrangements to the cell surface. Intermediate filaments of different molecular classes are char -
acteristic of particular tissues or states of maturity and are therefore important indicators of the origins of cells or degrees of differentiation, as well as being of considerable value in histopathology.
Intermediate filament proteins have been classified into five distinct
types on the basis of their primary structure and tissue-specific expres - | 50 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
15.e1
CHaPTER 1
A-type lamins include lamin A (interacting with emerin), lamin C,
lamin C2 and lamin AΔ10 encoded by a single gene (LMNA). Lamin A
and lamin C are the major A-type lamins expressed in somatic cells, whereas lamin C2 is expressed in testis. B-type lamins include lamin B1 and lamin B2 (expressed in somatic cells), and testis-specific lamin
B3. Lamin B1 is encoded by the LMNB1 gene; lamin B2 is encoded by
the LMNB2 gene. | 51 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
16 SECTION 1
permeable to small molecules, ions and proteins up to about 17 kDa.
See Raices and D’Angelo (2012) for further reading on nuclear pore
complex composition. Most proteins that enter the nucleus do so as
complexes with specific transport receptor proteins known as import -
ins. Importins shuttle back and forth between the nucleus and cyto -
plasm. Binding of the cargo to the importin requires a short sequence
of amino acids known as a nuclear localization sequence (NLS), and
can either be direct or take place via an adapter protein. Interactions of
the importin with components of the nuclear pore move it, together
with its cargo, through the pore by an energy-independent process.
A complementary cycle functions in export of proteins and RNA mol-ecules from the nucleus to the cytoplasm using transport receptors
known as exportins.
A small GTPase called Ras-related nuclear protein (Ran) regulates the
import and export of proteins across the nuclear envelope.
For further reading on the Ran pathway and exportins/importins, see
Clarke and Zhang (2008) and Raices and D’Angelo (2012).
Chromatin
DNA is organized within the nucleus in a DNA–protein complex known as chromatin. The protein constituents of chromatin are the histones
and the non-histone proteins. Non-histone proteins are an extremely
heterogeneous group that includes structural proteins, DNA and RNA
polymerases, and gene regulatory proteins. Histones are the most abun -
dant group of proteins in chromatin, primarily responsible for the packaging of chromosomal DNA into its primary level of organization,
the nucleosome. There are four core histone proteins – H2A, H2B, H3
and H4 – which combine in equal ratios to form a compact octameric
nucleosome core. A fifth histone, H1, is involved in further compaction
of the chromatin. The DNA molecule (one per chromosome) winds
twice around each nucleosome core, taking up 165 nucleotide pairs.
This packaging organizes the DNA into a chromatin fibre 1 1 nm in
diameter, and imparts to this form of chromatin the electron micro -
scopic appearance of beads on a string, in which each bead is separated
by a variable length of DNA, typically about 35 nucleotide pairs long.
The nucleosome core region and one of the linker regions constitute
the nucleosome proper, which is typically about 200 nucleotide pairs
in length. However, chromatin rarely exists in this simple form and is
usually packaged further into a 30 nm thick fibre, involving a single H1
histone per nucleosome, which interacts with both DNA and protein
to impose a higher order of nucleosome packing. Usually, 30 nm thick
fibres are further coiled or folded into larger domains. Individual domains are believed to decondense and extend during active transcrip-
tion. In a typical interphase nucleus, euchromatin (nuclear regions that
appear pale in appropriately stained tissue sections, or relatively
electron-lucent in electron micrographs; see Fig. 1.2) is likely to consist
mainly of 30 nm fibres and loops, and contains the transcriptionally
active genes. Transcriptionally active cells, such as most neurones, have
nuclei that are predominantly euchromatic. See Luger et al (2012) for
further reading on the nucleosome and chromatin structure.
Heterochromatin (nuclear regions that appear dark in appropriately
stained tissue sections or electron-dense in electron micrographs) is
characteristically located mainly around the periphery of the nucleus,
except over the nuclear pores (see Fig. 1.1 1A), and adjacent to the
nucleolus (see Fig. 1.2). It is a relatively compacted form of chromatin
in which the histone proteins carry a specific set of post-translational
modifications, including methylation at characteristic residues. This
facilitates the binding of specific heterochromatin-associated proteins.
Heterochromatin includes non-coding regions of DNA, such as centro -
meric regions, which are known as constitutive heterochromatin. DNA becomes transcriptionally inactive in some cells as they differentiate
during development or cell maturation, and contributes to heterochro-
matin; it is known as facultative heterochromatin. The inactive X chro-
mosome in females is an example of facultative heterochromatin and
can be identified in the light microscope as the deeply staining Barr
body often located near the nuclear periphery or a drumstick extension
of a nuclear lobe of a mature multilobed neutrophil leukocyte.
In transcriptionally inactive cells, chromatin is predominantly in the
condensed, heterochromatic state, and may comprise as much as 90%
of the total. Examples of such cells are mature neutrophil leukocytes
(in which the condensed chromatin is present in a multilobular, densely
staining nucleus) and the highly condensed nuclei of orthochromatic
erythroblasts (late-stage erythrocyte precursors). In most mature cells, a mixture of the two occurs, indicating that only a proportion of the DNA is being transcribed. A particular instance of this is seen in the B lymphocyte-derived plasma cell, in which much of the chromatin is in the condensed condition and is arranged in regular masses around the perimeter of the nucleus, producing the so-called ‘clock-face’ nucleus (see Figs 4.6, 4.12). Although this cell is actively transcribing, much of surprisingly wide range of diseases, from progeria to various dystro -
phies, including an autosomal dominant form of EDMD. A truncated
farnesylated form of lamin A, referred to as progerin, leads to defects
in cell proliferation and DNA damage of mesenchymal stem cells and
vascular smooth muscle cells. Affected patients display cardiovascular
disease and die at an early age. Mice lacking lamin B1 and lamin B2
survive until birth; however, neuronal development is compromised
when lamin B1 or lamin B2 is absent. Overexpression of lamin B1 is
associated with autosomal dominant leukodystrophy characterized by
gradual demyelination in the central nervous system. See Worman
(2012) and Burke and Stewart (2013) for additional reading on lamins
and laminopathies.
Condensed chromatin (heterochromatin) tends to aggregate near
the nuclear envelope during interphase. At the end of mitotic and
meiotic prophase (see below), the lamin filaments disassemble by
phosphorylation, causing the nuclear membranes to vesiculate and
disperse into the endoplasmic reticulum. During the final stages of
mitosis (telophase), proteins of the nuclear periphery, including lamins,
associate with the surface of the chromosomes, providing docking sites
for membrane vesicles. Fusion of these vesicles reconstitutes the nuclear
envelope, including the nuclear lamina, following lamin dephosphor -
ylation. See Simon and Wilson (201 1) for further reading on the
nucleoskeleton.
The transport of molecules between the nucleus and the cytoplasm
occurs via specialized nuclear pore structures that perforate the nuclear
membrane (Fig. 1.1 1A). They act as highly selective directional molecu -
lar filters, permitting proteins such as histones and gene regulatory proteins (which are synthesized in the cytoplasm but function in the
nucleus) to enter the nucleus, and molecules that are synthesized in the
nucleus but destined for the cytoplasm (e.g. ribosomal subunits, trans -
fer RNAs and messenger RNAs) to leave the nucleus.
Ultrastructurally, nuclear pores appear as disc-like structures with an
outer diameter of 130 nm and an inner pore with an effective diameter
for free diffusion of 9 nm ( Fig. 1.1 1B). The nuclear envelope of an
active cell contains up to 4000 such pores. The nuclear pore complex
has an octagonal symmetry and is formed by an assembly of more than
50 proteins, the nucleoporins. The inner and outer nuclear membranes
fuse around the pore complex (see Fig. 1.1 1A). Nuclear pores are freely
Fig . 1 .11 A, The nuclear envelope with nuclear pores (arrows) in
transverse section, showing the continuity between the inner and outer
phospholipid layers of the envelope on either side of the pore . The fine
‘membrane’ appearing to span the pore is formed by proteins of the pore
complex . Note that the chromatin is less condensed in the region of
nuclear pores . Abbreviations: N, nucleus; C, cytoplasm . B, Nuclear pores
seen ‘en face ’ as spherical structures (arrows) in a tangential section
through the nuclear envelope . The appearance of the envelope varies in
electron density as the plane of section passes through different regions
of the curved double membrane, which is interrupted at intervals by pores
through the envelope (see also Fig . 1 .1) . The surrounding cytoplasm with
ribosomes is less electron-dense . Human tissues . (Courtesy of Dr Bart
Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .)
N
CA
B | 52 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell structure
17
CHaPTER 1
easily seen during metaphase, although prophase chromosomes can be
used for more detailed analyses.
Lymphocytes separated from blood samples, or cells taken from
other tissues, are used as a source of chromosomes. Diagnosis of fetal
chromosome patterns is generally carried out on samples of amniotic
fluid containing fetal cells aspirated from the uterus by amniocentesis,
or on a small piece of chorionic villus tissue removed from the placenta.
Whatever their origin, the cells are cultured in vitro and stimulated to
divide by treatment with agents that stimulate cell division. Mitosis is interrupted at metaphase with spindle inhibitors. The chromosomes are
dispersed by first causing the cells to swell in a hypotonic solution, then
the cells are gently fixed and mechanically ruptured on a slide to spread
the chromosomes. They are subsequently stained in various ways to
allow the identification of individual chromosomes by size, shape and
distribution of stain (Fig. 1.12). General techniques show the obvious
landmarks, e.g. lengths of arms and positions of constrictions. Banding
techniques demonstrate differential staining patterns, characteristic for
each chromosome type. Fluorescence staining with quinacrine mustard
and related compounds produces Q bands, and Giemsa staining (after
treatment that partially denatures the chromatin) gives G bands ( Fig.
1.12A). Other less widely used methods include: reverse Giemsa stain -
ing, in which the light and dark areas are reversed (R bands); the stain -
ing of constitutive heterochromatin with silver salts (C-banding); and T-banding to stain the ends (telomeres) of chromosomes. Collectively,
these methods permit the classification of chromosomes into num -
bered autosomal pairs in order of decreasing size, from 1 to 22, plus the sex chromosomes.
A summary of the major classes of chromosome is given in
Table 1.1.
Methodological advances in banding techniques improved the re -
cognition of abnormal chromosome patterns. The use of in situ hybridi-
zation with fluorescent DNA probes specific for each chromosome ( Fig.
1.12B) permits the identification of even very small abnormalities.
Nucleolus
Nucleoli are a prominent feature of an interphase nucleus (see Fig. 1.2).
They are the site of most of the synthesis of ribosomal RNA (rRNA) and
assembly of ribosome subunits. Nucleoli organize at the end of mitosis its protein synthesis is of a single immunoglobulin type, and conse -
quently much of its genome is in an inactive state.
During mitosis, the chromatin is further reorganized and condensed
to form the much-shortened chromosomes characteristic of metaphase. This shortening is achieved through further levels of close packing of
the chromatin. The condensed chromosomes are stabilized by protein
complexes known as condensins. Progressive folding of the chromo -
somal DNA by interactions with specific proteins can reduce 5 cm of
chromosomal DNA by 10,000-fold, to a length of 5 µm in the mitotic
chromosome.
Chromosomes and telomeres
The nuclear DNA of eukaryotic cells is organized into linear units called
chromosomes. The DNA in a normal human diploid cell contains
6 × 109 nucleotide pairs organized in the form of 46 chromosomes (44
autosomes and 2 sex chromosomes). The largest human chromosome
(number 1) contains 2.5 × 108 nucleotide pairs, and the smallest (the Y
chromosome) 5 × 107 nucleotide pairs.
Each chromosomal DNA molecule contains a number of specialized
nucleotide sequences that are associated with its maintenance. One is the centromeric DNA region. During mitosis, a disc-shaped structure
composed of a complex array of proteins, the kinetochore, forms as a
substructure at the centromeric region of DNA to which kinetochore
microtubules of the spindle attach. Another region, the telomere,
defines the end of each chromosomal DNA molecule. Telomeres consist
of hundreds of repeats of the nucleotide sequence (TTAGGG)
n. The very
ends of the chromosomes cannot be replicated by the same DNA polymerase as the rest of the chromosome, and are maintained by a
specific enzyme called telomerase, which contains an RNA subunit
acting as the template for lengthening the TTAGGG repeats. See
Nandakumar and Cech (2013) for further reading on the recruitment of telomerase to telomeres. Thus telomerase is a specialized type of
polymerase known as a reverse transcriptase that turns sequences in
RNA back into DNA. The number of tandem repeats of the telomeric
DNA sequence varies. The telomere appears to shorten with successive
cell divisions because telomerase activity reduces or is absent in dif-
ferentiated cells with a finite lifespan. In mammals, telomerase is active
in the germ-cell lineage and in stem cells, but its expression in somatic
cells may lead to or prompt cancer. A lack of telomere maintenance
determines the shrinking of telomeres in proliferating cells to the point
when cells stop dividing, a condition known as replicative senescence.
See Sahin and DePinho (2012) for further reading on telomeres and
progressive DNA damage.
The role of the telomere in ageing and cell senescence is further
discussed at the end of this chapter.
Karyotypes: classification of human chromosomes
A number of genetic abnormalities can be directly related to the chro -
mosomal pattern. The characterization or karyotyping of chromosome number and structure is therefore of considerable diagnostic impor -
tance. The identifying features of individual chromosomes are most
Fig . 1 .12 Chromosomes from normal males, arranged as karyotypes . A, G-banded preparation . B, Preparation stained by multiplex fluorescence in situ
hybridization to identify each chromosome . (Courtesy of Dr Denise Sheer, Cancer Research UK .)
1
6
13
19 20 21 22 X Y14 15 16 17 187 8 9 10 11 122 3 4 5
A
1
6 7 8 9 10 11 12
18 17 16 15 14 13
19 20 21 22 X Y2 3 4 5
BTable 1.1 Summary of the major classes of chromosome
Group Features
1–3 (A) Large metacentric chromosomes
4–5 (B) Large submetacentric chromosomes
6–12 + X (C) Metacentrics of medium size
13–15 (D) Medium-sized acrocentrics with satellites
16–18 (E) Shorter metacentrics (16) or submetacentrics (17,18)
19–20 (F) Shortest metacentrics
21–22 + Y (G) Short acrocentrics; 21, 22 with satellites, Y without | 53 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
17.e1
CHaPTER 1
Telomerase has been associated with ageing and cell senescence
because a gradual loss of telomeres may lead to tissue atrophy, stem
cell depletion and deficient tissue repair or regeneration. Mutations causing loss of function of telomerase or the RNA-containing template have been associated with dyskeratosis congenita (characterized by
abnormal skin pigmentation, nail dystrophy and mucosal leukoplasia),
aplastic anaemia and pulmonary fibrosis. | 54 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
18 SECTION 1
certain tumour suppressor genes (e.g. the gene mutated in retinoblas -
toma, Rb) block the cycle in G 1. DNA synthesis (replication of the
genome) occurs during S phase, at the end of which the DNA content
of the cell has doubled. During G 2, the cell prepares for division; this
period ends with the onset of chromosome condensation and break -
down of the nuclear envelope. The times taken for S, G 2 and M are
similar for most cell types, and occupy 6–8, 2–4 and 1–2 hours respec -
tively. In contrast, the duration of G 1 shows considerable variation,
sometimes ranging from less than 2 hours in rapidly dividing cells to more than 100 hours, within the same tissue.
The passage of a cell through the cell cycle is controlled by proteins
in the cytoplasm: cyclins and cyclin-dependent kinases (Cdks; Fig
1.13). Cyclins include G
1 cyclins (D cyclins), S-phase cyclins (cyclins E
and A) and mitotic cyclins (B cyclins). Cdks, protein kinases, which are activated by binding of a cyclin subunit, include G
1 Cdk (Cdk4), an
S-phase Cdk (Cdk2) and an M-phase Cdk (Cdk1). Cell cycle progres -
sion is driven in part by changes in the activity of Cdks. Each cell cycle
stage is characterized by the activity of one or more Cdk–cyclin pairs.
Transitions between cell cycle stages are triggered by highly specific
proteolysis by the 26S proteasome of the cyclins and other key
components.
To give one example, the transition from G 2 to mitosis is driven by
activation of Cdk1 by its partners, the A- and B-type cyclins; the char -
acteristic changes in cellular structure that occur as cells enter mitosis
are largely driven by phosphorylation of proteins by active Cdk1-cyclin
A and Cdk1-cyclin B. Cells exit from mitosis when an E3 ubiquitin
ligase, the anaphase promoting complex, also called cyclosome
(APC/C), marks the cyclins for destruction. In addition, APC/C prompts
the degradation of the mitotic cyclin B and the destruction of cohesins,
thus allowing sister chromatids to separate.
There are important checkpoints in the cell cycle (see Fig. 1.13).
Checkpoint 1 requires G 1 cyclins to bind to their corresponding Cdks
to signal the cell to prepare for DNA synthesis. S-phase promoting
factor (SPF; cyclin A bound to Cdk2) enters the nucleus to stimulate
DNA synthesis. Checkpoint 2 requires M-phase promoting factor (mitotic cyclin B bound to M-phase Cdk1) to trigger the assembly of the mitotic spindle, breakdown of the nuclear envelope, arrest of gene transcription and condensation of chromosomes. During metaphase of mitosis, M-phase promoting factor activates APC/C, which determines the breakdown of cohesins, the protein complex holding sister chroma -
tids together. Then, at anaphase, separated chromatids move to the opposite poles of the spindle. Finally, B cyclins are destroyed following and consist of repeated clusters of ribosomal DNA (rDNA) genes and
processing molecules responsible for producing ribosome subunits. The
initial step of the assembly of a ribosome subunit starts with the tran -
scription of rDNA genes by RNA polymerase I. The rDNA genes, arranged in tandem repeats called nucleolar organizing regions (NORs),
are located on acrocentric chromosomes. There are five pairs of acro -
centric chromosomes in humans. The initial 47S rRNA precursor tran -
script is cleaved to form the mature 28S, 18S and 5.8S rRNAs, assembled
with the 5S rRNA (synthesized by RNA polymerase III outside the
nucleolus) and coupled to small nucleolar ribonucleoproteins and
other non-ribosomal proteins to form 60S (containing 28S rRNA, 5.8S
rRNA and 5S rRNA) and 40S (containing 18S rRNA) preribosome sub -
units. These are then exported to the cytoplasm across nuclear pores as
mature ribosome subunits. About 726 human nucleolar proteins have
been identified by protein purification and mass spectrometry. For
further reading on nucleolar functions, see Boisvert et al (2007).
Ribosomal biogenesis occurs in distinct subregions of the nucleolus,
visualized by electron microscopy. The three nucleolar subregions are fibrillar centres (FCs), dense fibrillar components (DFCs) and granular
components (GCs). Transcription of the rDNA repeats takes place at
the FC-DFC boundary; pools of RNA polymerase I reside in the FC
region; processing of transcripts and coupling to small nucleolar ribo -
nucleoproteins take place in DFC; and the assembly of ribosome sub -
units is completed in the GC region.
The nucleolus is disassembled when cells enter mitosis and tran -
scription becomes inactive. It reforms after nuclear envelope reorganiza -
tion in telophase, in a process associated with the onset of transcription
in nucleolar organizing centres on each specific chromosome, and
becomes functional during the G 1 phase of the cell cycle. An adequate
pool of ribosome subunits during cell growth and cell division requires
steady nucleolar activity to support protein synthesis. Several DNA
helicases, a conserved group of enzymes that unwind DNA, accumulate
in the nucleolus under specific conditions such as Bloom’s syndrome
(an autosomal recessive disorder characterized by growth deficiency,
immunodeficiency and a predisposition to cancer) and Werner’s syn -
drome (an autosomal recessive condition characterized by the early appearance of various age-related diseases).
CELL DIVISION AND THE CELL CYCLE
During prenatal development, most cells undergo repeated division (see Video 1.1) as the body grows in size and complexity. As cells
mature, they differentiate structurally and functionally. Some cells, such
as neurones, lose the ability to divide. Others may persist throughout
the lifetime of the individual as replication-competent stem cells, e.g.
cells in the haemopoietic tissue of bone marrow. Many stem cells divide
infrequently, but give rise to daughter cells that undergo repeated cycles
of mitotic division as transit (or transient) amplifying cells. Their divi -
sions may occur in rapid succession, as in cell lineages with a short lifespan and similarly fast turnover and replacement time. Transit
amplifying cells are all destined to differentiate and ultimately to die
and be replaced, unlike the population of parental stem cells, which
self-renews.
Patterns and rates of cell division within tissues vary considerably.
In many epithelia, such as the crypts between intestinal villi, the replace -
ment of damaged or ageing cells by division of stem cells can be rapid. Rates of cell division may also vary according to demand, as occurs in
the healing of wounded skin, in which cell proliferation increases to a
peak and then returns to the normal replacement level. The rate of cell
division is tightly coupled to the demand for growth and replacement.
Where this coupling is faulty, tissues either fail to grow or replace their
cells, or they can overgrow, producing neoplasms.
The cell cycle is an ordered sequence of events, culminating in cell
growth and division to produce two daughter cells. It generally lasts a
minimum of 12 hours, but in most adult tissues can be considerably
longer, and is divided into four distinct phases, which are known as G
1
(for gap 1), S (for DNA synthesis), G 2 (for gap 2) and M (for mitosis).
The combination of G 1, S and G 2 phases is known as interphase. M is
the mitotic phase, which is further divided into four phases (see below).
G1 is the period when cells respond to growth factors directing the cell
to initiate another cycle; once made, this decision is irreversible. It is
also the phase in which most of the molecular machinery required to complete another cell cycle is generated. Centrosomes duplicate during S phase in preparation for mitosis. Cells that retain the capacity for proliferation, but which are no longer dividing, have entered a phase called G
0 and are described as quiescent even though they may be quite
active physiologically. Growth factors can stimulate quiescent cells to leave G
0 and re-enter the cell cycle, whereas the proteins encoded by
Fig . 1 .13 The cell cycle consists of an interphase (G 1 phase, S phase and
G2 phase) followed by mitosis . The cyclin D/Cdk4 complex assembles at
the beginning of G 1; the cyclin E/Cdk2 complex assembles near the end
of G 1 as the cell is preparing to cross checkpoint 1 to start DNA synthesis
(during S phase) . The cyclin A/Cdk2 complex assembles as DNA
synthesis starts . Completion of G 2 is indicated by the assembled cyclin A/
Cdk1 complex . A cell crosses checkpoint 2 to initiate mitosis when the
cyclin B/Cdk1 complex assembles . The cyclin B/Cdk1 complex is
degraded by the 26S proteasome and an assembled cyclin D/Cdk4 marks
the start of the G 1 phase of a new cell cycle . For details, see text .
(Modified with permission from Kierszenbaum AL, Tres LL . Histology and
Cell Biology: An Introduction to Pathology . 3rd ed, Philadelphia: Elsevier,
Saunders; 2011 .)Cyclin ACyclin D
Cyclin ECyclin A
Cdk2 Cdk4
Cdk2Cdk1
Mitosis
SCyclin BCdk1G2
G1Checkpoint 1Checkpoint 2 | 55 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
18.e1
CHaPTER 1
The targets for proteolysis are marked for destruction by E3 ubiquitin
ligases, which decorate them with polymers of the small protein ubiq -
uitin, a sign for recognition by the 26S proteasome. | 56 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell division and the cell cycle
19
CHaPTER 1
their attachment to ubiquitin, targeting them for destruction by the 26S
proteasome. As G 1 starts, cyclins D, bound to Cdk4, start preparation
for a new cell cycle.
Quality control checkpoint 2 operates to delay cell-cycle progression
when DNA has been damaged by radiation or chemical mutagens. Cells
with checkpoint defects, such as loss of the protein p53, which is a
major negative control element in the division cycle of all cells, are
commonly associated with the development of malignancy. An example
is Li Fraumeni syndrome, where a defective p53 gene leads to a high
frequency of cancer in affected individuals. In cells, p53 protein binds DNA and stimulates another gene to produce p21 protein, which inter -
acts with Cdk2 to prevent S-phase promoting activity. When mutant p53 can no longer bind DNA to stimulate production of p21 to stop
DNA synthesis, cells acquire oncogenic properties. The p53 gene is an
example of a tumour suppressor gene. For further reading on p53 muta-
tions and cancer, see Muller and Vousden (2013).
Mitosis and meiosis
Mitosis is the process that results in the distribution of identical copies of the parent cell genome to the two daughter somatic cells. In meiosis,
the divisions immediately before the final production of gametes halve
the number of chromosomes to the haploid number, so that at fertiliza -
tion the diploid number is restored. Moreover, meiosis includes a phase in which exchange of genetic material occurs between homologous
chromosomes. This allows a rearrangement of genes to take place,
which means that the daughter cells differ from the parental cell in both
their precise genetic sequence and their haploid state. Mitosis and
meiosis are alike in many respects, and differ principally in chromo -
somal behaviour during the early stages of cell division. In meiosis, two divisions occur in succession, without an intervening S phase. Meiosis
I is distinct from mitosis, whereas meiosis II is more like mitosis.
Mitosis
New DNA is synthesized during the S phase of the cell cycle interphase. This means that the amount of DNA in diploid cells has doubled to
the tetraploid value by the onset of mitosis, although the chromosome
number is still diploid. During mitosis, this amount is halved between
the two daughter cells, so that DNA quantity and chromosome number
are diploid in both cells. The cellular changes that achieve this distribu -
tion are conventionally divided into four phases called prophase, meta -
phase, anaphase and telophase ( Figs 1.14–1.15, Video 1.1).
Prophase
During prophase, the strands of chromatin, which are highly extended
during interphase, shorten, thicken and resolve themselves into recog -
nizable chromosomes. Each chromosome is made up of duplicate chro -
matids (the products of DNA replication) joined at their centromeres.
Outside the nucleus, the two centriole pairs begin to separate, and move
towards opposite poles of the cell. Parallel microtubules are assembled
between them to create the mitotic spindle, and others radiate to form
the microtubule asters, which come to form the spindle poles or mitotic
centre. As prophase proceeds, the nucleoli disappear, and the nuclear
envelope suddenly disintegrates to release the chromosomes, an event
that marks the end of prophase.
Prometaphase–metaphase
As the nuclear envelope disappears, the spindle microtubules extend into the central region of the cell, attaching to the chromosomes, which
subsequently move towards the equator of the spindle (prometaphase).
The spindle consists of kinetochore microtubules attached to the kine -
tochore, a multiprotein structure assembled at the centromeric DNA region, and polar microtubules, which are not attached to chromo -
somes but instead overlap with each other at the centre of the cell. The
grouping of chromosomes at the spindle equator is called the meta -
phase or equatorial plate. The chromosomes, attached at their centro -
meres, appear to be arranged in a ring when viewed from either pole of the cell, or to lie linearly across this plane when viewed from above.
Cytoplasmic movements during late metaphase effect the approxi-
mately equal distribution of mitochondria and other cell structures
around the cell periphery.
anaphase
By the end of metaphase every chromosome consists of a pair of sister
chromatids attached to opposing spindle poles by bundles of microtu -
bules associated with the kinetochore. The onset of anaphase begins with the proteolytic cleavage by the enzyme separase of a key subunit of protein complexes known as cohesins. The latter hold the replicated sister chromatids together to resist separation even when exposed to
Fig . 1 .14 The stages in mitosis, including the appearance and distribution
of the chromosomes . Prophase
Nuclear
membrane
Centromere
Two sister
chromatidsattached at
centromereMicrotubules
of spindleCentriole centre
of aster (or spindle pole)
Prometaphase
Spindle pole
Nuclear
membrane
vesiclesMicrotubule
Metaphase
Cell equator
Anaphase
Chromatids pulled
toward pole of spindle
as their microtubules
shorten
Telophase
Nuclear membrane
reformsChromosomes decondense and
detach from microtubules
Cytokinesis
Nuclear
membraneCentriole
Actin–myosin belt
microtubule-dependent pulling forces. Proteolytic cleavage releases the
cohesion between sister chromatids, which then move towards opposite spindle poles while the microtubule bundles attached to the kineto -
chores shorten and move polewards. At the end of anaphase the sister chromatids are grouped at either end of the cell, and both clusters are | 57 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
20 SECTION 1
diploid in number. An infolding of the cell equator begins, deepening
during telophase as the cleavage furrow.
Telophase
During telophase the nuclear envelopes reform, beginning with the association of membranous vesicles with the surface of the chromo -
somes. Later, after the vesicles have fused and the nuclear envelope is complete, the chromosomes decondense and the nucleoli reform. At
the same time, cytoplasmic division, which usually begins in early
anaphase, continues until the new cells separate, each with its derived
nucleus. The spindle remnant now disintegrates. While the cleavage
furrow is active, a peripheral band or belt of actin and myosin appears
in the constricting zone; contraction of this band is responsible for
furrow formation.
Failure of disjunction of chromatids, so that sister chromatids pass
to the same pole, may sometimes occur. Of the two new cells, one will
have more, and the other fewer, chromosomes than the diploid number.
Exposure to ionizing radiation promotes non-disjunction and may, by
chromosomal damage, inhibit mitosis altogether. A typical symptom of
radiation exposure is the failure of rapidly dividing epithelia to replace
lost cells, with consequent ulceration of the skin and mucous mem-
branes. Mitosis can also be disrupted by chemical agents, particularly
vinblastine, paclitaxel (taxol) and their derivatives. These compounds
either disassemble spindle microtubules or interfere with their dynam -
ics, so that mitosis is arrested in metaphase.
Meiosis
There are two consecutive cell divisions during meiosis: meiosis I and meiosis II ( Fig. 1.16). Details of this process differ at a cellular level for
male and female lineages.Fig . 1 .15
Immunofluorescence
images of stages in
mitosis in human
carcinoma cells in
culture . A, Metaphase,
with spindle
microtubules (green),
the microtubule-
stabilizing protein
(HURP; red) and
chromosomal DNA
(blue) . B, Anaphase,
with spindle microtubules (green),
the central spindle
(Aurora-B kinase, red)
and segregated
chromosomes (blue) .
C, Late anaphase, with
spindle microtubules
(green), the central
spindle (Plk1 kinase,
red, appearing yellow
where co-localized with
microtubule protein)
and segregated
chromosomes (blue) .
(Courtesy of Dr Herman
Silljé, Max-Planck-
Institut für Biochemie,
Martinsried, Germany .)
A
B
C
Fig . 1 .16 The stages in meiosis, depicted by two pairs of maternal and paternal homologues (dark and pale colours) . DNA and chromosome
complement changes and exchange of genetic information between homologues are indicated . Pairing of
paternal and
maternal
homologuesBA Events preceding meiosis
B Meiotic prophase
C Meiosis I
D Meiosis IIPremeiotic
S phaseCentromere
Meiotic
prophasePaired sister
centromeres
Meiosis I
Leptotene Zygotene Pachytene Diplotene DiakinesisAa
bA
a
bB
Metaphase I Anaphase I
Prophase II Metaphase IIA
aB
bA
a bBChiasmata
Meiosis I Meiosis II
Interphase
(no S phase)A
bB
a
A
aB
b
Anaphase II Haploid gametes | 58 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell polarity and domains
21
CHaPTER 1
equatorial plane of the spindle. The centromeres of each pair of sister
chromatids function as a single unit, facing a single spindle pole.
Homologous chromosomes are pulled towards opposite spindle poles,
but are held paired at the spindle midzone by chiasmata. Errors in
chromosome segregation (known as non-disjunction) lead to the pro-
duction of aneuploid progeny. Most human aneuploid embryos are
non-viable and this is the major cause of fetal loss (spontaneous abor -
tion), particularly during the first trimester of pregnancy in humans. The most common form of viable aneuploid progeny in humans is
Down’s syndrome (trisomy for chromosome 21), which exhibits a dra-
matic increase with maternal age.
Anaphase and telophase I
Anaphase I of meiosis begins with the release of cohesion between the
arms of sister chromatids, much as it does during mitosis. As position -
ing of bivalent pairs is random, assortment of maternal and paternal chromosomes in each telophase nucleus is also random. Critically,
sister centromeres, and thus chromatids, do not separate during ana-
phase I.
During meiosis I, cytoplasmic division occurs by specialized mecha -
nisms. In females, the division is highly asymmetric, producing one egg
and one tiny cell known as a polar body. In males, the process results
in production of spermatocytes that remain joined by small cytoplas -
mic bridges.
meiosis II
Meiosis II commences after only a short interval during which no DNA
synthesis occurs. The centromeres of sister chromatids remain paired,
but rotate so that each one can face an opposite spindle pole. Onset of
anaphase II is triggered by loss of cohesion between the centromeres,
as it is in mitosis. This second division is more like mitosis, in that
chromatids separate during anaphase, but, unlike mitosis, the separat -
ing chromatids are genetically different (the result of genetic recombi -
nation). Cytoplasmic division also occurs and thus, in the male, four
haploid cells, interconnected by cytoplasmic bridges, result from
meiosis I and II.
CELL POLARITY AND DOMAINS
Epithelia are organized into sheets or glandular structures with very
different environments on either side. These cells actively transfer mac-
romolecules and ions between the two surfaces and are thus polarized
in structure and function. In polarized cells, particularly in epithelia,
the cell is generally subdivided into domains that reflect the polariza -
tion of activities within it. The free surface, e.g. that facing the intestinal lumen or airway, is the apical surface, and its adjacent cytoplasm is the
apical cell domain. This is where the cell interfaces with a specific body
compartment (or, in the case of the epidermis, with the outside world).
The apical surface is specialized to act as a barrier, restricting access of
substances from this compartment to the rest of the body. Specific
components are selectively absorbed from, or added to, the external
compartment by the active processes, respectively, of active transport
and endocytosis inwardly or exocytosis and secretion outwardly.
The apical surface is often covered with small protrusions of the cell surface, microvilli, which increase the surface area, particularly for
absorption.
The surface of the cell opposite to the apical surface is the basal
surface, with its associated basolateral cell domain. In a single-layered
epithelium, this surface faces the basal lamina. The remaining surfaces
are known as the lateral cell surfaces. In many instances, the lateral and
basal surfaces perform similar functions and the cellular domain is
termed the basolateral domain. Cells actively transport substances, such
as digested nutrients from the intestinal lumen or endocrine secretions,
across their basal (or basolateral) surfaces into the subjacent connective
tissue matrix and the blood capillaries within it. Dissolved non-polar
gases (oxygen and carbon dioxide) diffuse freely between the cell and
the blood stream across the basolateral surface. Apical and basolateral
surfaces are separated by a tight intercellular seal, the tight junction
(occluding junction, zonula adherens), which prevents the passage of
even small ions through the space between adjacent cells and thus
maintains the difference between environments on either side of the
epithelium.
Cell surface apical differentiations
The surfaces of many different types of cell are specialized to form structures that project from the surface. These projections may permit meiosis I
Prophase I
Meiotic prophase I is a long and complex phase that differs consider -
ably from mitotic prophase and is customarily divided into five sub -
stages, called leptotene, zygotene, pachytene, diplotene and diakinesis.
There are three distinctive features of male meiotic prophase that are
not seen during mitotic prophase: the pairing, or synapse, of homolo -
gous chromosomes of paternal and maternal origin to form bivalent structures; the organization of nucleoli by autosomal bivalents; and
significant non-ribosomal RNA synthesis by autosomal bivalents (in
contrast to the transcriptional inactivity of the XY chromosomal pair)
(see Tres 2005). In the female, meiotic prophase I starts during fetal
gonadogenesis, is arrested at the diplotene stage and resumes at puberty. In the male, meiosis starts at puberty.
Leptotene stage During leptotene, homologous chromosomes
(maternal and paternal copies of the same chromosome), replicated in
a preceding S phase and each consisting of sister chromatids joined at
the centromere (see above), locate one another within the nucleus, and
the process of genetic recombination is initiated. Cytologically, chro -
mosomes begin to condense, appearing as individual threads that are attached via their telomeres to the nuclear envelope. They often show
characteristic beading throughout their length.
Zygotene stage During zygotene, the homologous chromosomes
initiate pairing or synapsis, during which they become intimately asso -
ciated with one another. Synapsis may begin near the telomeres at the inner surface of the nuclear membrane, and during this stage the tel -
omeres often cluster to one side of the nucleus (a stage known as the bouquet because the chromosomes resemble a bouquet of flowers). The
pairs of synapsed homologues, also known as bivalents, are linked
together by a tripartite ribbon, the synaptonemal complex, which con -
sists of two lateral dense elements and a central, less dense, linear element.
The sex chromosomes also start to synapse during zygotene. In
males, with distinct X and Y chromosomes, synapsis involves a region
of shared DNA sequence known as the pseudoautosomal region. The
XY bivalent adopts a special condensed structure, known as the sex
vesicle, which becomes associated later at pachytene with migratory
nucleolar masses originating in the autosomal bivalents.
Chromosome behaviour in meiosis is intimately linked with the
process of genetic recombination. This begins during leptotene, as
homologous chromosomes first locate one another at a distance. Syn -
apsis, stabilized by the synaptonemal complex, facilitates recombina -
tion, as sites of genetic exchange are turned into specialized structures
known as chiasmata, which are topological crossing-over points that
hold homologous chromosomes together.
Pachytene stage When synapsis is complete for all chromosomes,
the cell is said to be in pachytene. Each bivalent looks like a single thick structure, but is actually two pairs of sister chromatids held together by
the synaptonemal complex. Genetic recombination between non-sister
chromatids is completed at this point, with sites where it has occurred
(usually one per chromosome arm) appearing as recombination
nodules in the centre of the synaptonemal complex.
Diplotene stage During diplotene, the synaptonemal complex disas -
sembles and pairs of homologous chromosomes, now much shortened, separate, except where crossing over has occurred (chiasmata). This
process is called disjunction. At least one chiasma forms between each
homologous pair, exchanging maternal and paternal sequences; up to
five have been observed. In the ovaries, primary oocytes become diplo -
tene by the fifth month in utero and each remains at this stage until the
period before ovulation (up to 50 years).
Diakinesis Diakinesis is the prometaphase of the first meiotic divi-
sion. The chromosomes, still as bivalents, become even shorter and
thicker. They gradually attach to the spindle and become aligned at a
metaphase plate. In eggs, the spindle forms without centrosomes.
Microtubules first nucleate and are stabilized near the chromosomes;
the action of various motor molecules eventually sorts them into a
bipolar spindle. Perhaps surprisingly, this spindle is as efficient a
machine for chromosome segregation as the spindle of mitotic cells with centrosomes at the poles.
Metaphase I
Metaphase I resembles mitotic metaphase, except that the bodies attach -
ing to the spindle microtubules are bivalents, not single chromosomes. These become arranged so that the homologous pairs occupy the | 59 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
22 SECTION 1
its distal region, called the transition zone. The continued elongation
of the cilium requires the import and intraciliary transport of tubulin
dimers to the distal tip by bidirectional motor-driven proteins of the
intraflagellar transport complex.
The constant length of cilia is maintained by a steady-state balance
between tubulin turnover and addition of new tubulin dimers at the
ciliary tip.
Several filamentous structures are associated with the 9 + 2 doublet
microtubule of the axoneme in the cilium or flagellum shaft, e.g. radial
spokes extend inwards from the outer doublet microtubules towards
the central pair, surrounded by an inner sheath (see Fig. 1.17). The outer
doublet microtubules bear two rows of tangential dynein arms attached to the complete A subfibre of the doublet (consisting of 13 protofila -
ments), which point towards the incomplete B subfibre of the adjacent doublet (consisting of 10–1 1 protofilaments). Adjacent doublets are
also linked by thin nexin filaments. Tektins are scaffolding filamentous
proteins extending along the axonemal microtubules.
In motile cilia, arrays of dynein arms with ATPase activity cause outer
microtubule doublets to move past one another, resulting in a large-
scale bending motion. Microtubules do not change in length. Move -
ments of cilia and flagella are broadly similar. In addition to the axoneme, spermatozoan flagella have outer dense fibres and a fibrous
sheath surrounding the axoneme. Flagella move by rapid undulation,
which passes from the attached to the free end. In human spermatozoa,
there is an additional helical component to this motion. In cilia, the
beating is planar but asymmetric. In the effective stroke, the cilium
remains stiff except at the base, where it bends to produce an oar-like
stroke. The recovery stroke follows, during which the bend passes from
base to tip, returning the cilium to its initial position for the next cycle.
The activity of groups of cilia is usually coordinated so that the bending
of one is rapidly followed by the bending of the next and so on, movement of the cell itself (flagella), or of fluids across the apical cell
surface (cilia), or increase the surface area available for absorption
(microvilli). Infoldings of the basolateral plasma membrane also
increase the area for transport across this surface of the cell. In most
non-dividing epithelial cells, the centriole-derived basal body gives rise
to a non-motile primary cilium, which has an important mechanosen -
sory role.
Cilia and flagella
Cilia and flagella are motile, hair-like projections of the cell surface, which create currents in the surrounding fluid or movements of the cell
to which they are attached, or both. There are two categories of cilia:
single non-motile primary cilia and multiple motile cilia. Primary cilia
are immotile but can detect physical and biochemical signals. Motile
cilia are present in large numbers on the apical epithelial domain of
the upper respiratory tract and oviducts, and beat in a wave-like motion
to generate fluid movement. Cilia also occur, in modified form, at the
dendritic endings of olfactory receptor cells, vestibular hair cells (kino -
cilium), and the photoreceptor rods and cones of the retina. Flagella, with a primary function in cell locomotion, are found on single-cell
eukaryotes and in spermatozoa, which each possess a single flagellum
70 µm long.
A cilium or flagellum consists of a shaft (0.25 µm diameter) consti-
tuting most of its length, a tapering tip and a basal body at its base,
which lies within the surface cytoplasm of the cell ( Fig. 1.17). Other
than at its base, the entire structure of the cilium is covered by plasma membrane. The core of the cilium is the axoneme, a cylinder of nine
microtubule doublets that surrounds a central pair of single microtu -
bules (see Fig. 1.17). Ciliogenesis of primary cilia and motile cilia
involves distinct steps. A centriole-derived basal body migrates to the
apical cell domain and axonemal microtubule doublets emerge from
Fig . 1 .17 A, The structure of a cilium shown in longitudinal (left) and transverse (right) section . A and B are subfibres of the peripheral microtubule
doublets (see text); the basal body is structurally similar to a centriole, but with microtubule triplets . B, The apical region of respiratory epithelial cells,
showing the proximal parts of three cilia sectioned longitudinally, anchored into the cytoplasm by basal bodies (BB) . Other cilia project out of the plane
of section and are cut transversely, showing the ‘9 + 2’ arrangement of microtubules . (B, With permission from Young B, Heath JW . Wheater’s Functional
Histology . 4th ed . Edinburgh: Elsevier, Churchill Livingstone; 2000 .)Inner sheath
Central
microtubulesDynein ‘arms’
RootletA
Microtubule
doubletsNexin-linking
protein
Radial spokeAB
Tubulin subunits
Microtubule
tripletsPlasma membrane
Basal body
B
BBBB | 60 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
22.e1
CHaPTER 1
As indicated on page 15, the IFT-B protein complex participates in
intraciliary/intraflagellar anterograde transport of cargoes, a step essen-
tial for the assembly and maintenance of cilia and flagella; the IFT-A
protein complex is required for retrograde transport of cargoes to the
cell body for turnover. The movement of IFT proteins along microtu -
bules is catalysed by kinesin-2 (towards the ciliary tip; anterograde direction) and cytoplasmic dynein-2 motor proteins (towards the cell
body; retrograde direction). A cargo includes axonemal components,
ciliary/flagellar membrane proteins (including the BBSome) and ciliary
signal transduction proteins. | 61 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Cell polarity and domains
23
CHaPTER 1
resulting in long travelling waves of metachronal synchrony. These pass
over the tissue surface in the same direction as the effective stroke.
Ciliary motion is important in clearing mucus from airways, moving
eggs along oviducts, and circulating cerebrospinal fluid in brain ventri -
cles. In the node of the developing embryo, cilium-driven flow is essen -
tial for determining left–right visceral asymmetry (developing
patterning). Cilia also have a sensory function, determined by the pres -
ence of receptor and channel proteins on the ciliary membrane. Primary cilia in the collecting ducts of the uriniferous tubule sense the flow of
urine and also modulate duct morphogenesis. Cilia are essential for
signalling through the hedgehog pathway, a mechanism involved in
organizing the body plan, organogenesis and tumorigenesis in verte -
brates. For additional reading on hedgehog signalling and primary cilia, see Briscoe and Thérond (2013).
There is a group of genetic diseases in which cilia beat either inef -
fectively or not at all, e.g. Kartagener’s immotile cilia syndrome. Affected
cilia exhibit deficient function or a lack of dynein arms. Males are typi -
cally sterile because of the loss of spermatozoan motility, and half have an alimentary tract that is a mirror image of the usual pattern ( situs
inversus), i.e. it rotates in the opposite direction during early develop -
ment. Defects in ciliary motility disrupt airway mucus clearance, leading
to chronic sinusitis and bronchiectasis. Defects in sensory cilia deter -
mine polycystic kidney disease, anosmia and retinal degeneration.
Microvilli
Microvilli are finger-like cell surface extensions usually 0.1 µm in diam -
eter and up to 2 µm long ( Fig. 1.18).
Microvilli are covered by plasma membrane and supported inter -
nally by closely packed bundles of actin filaments linked by cross-bridges of the actin-bundling proteins, fascin and fimbrin. Other
bridges composed of myosin I and calmodulin connect the filament
bundles to the plasma membrane. At the tip of each microvillus, the
free ends of microfilaments are inserted into a dense mass that includes
the protein, villin. The actin filament bundles of microvilli are embed -
ded in the apical cytoplasm amongst a meshwork of transversely running actin filaments stabilized by spectrin to form the terminal web,
which is underlain by keratin intermediate filaments. The web is
anchored laterally to the tight junctions and zonula adherens of the
apical epithelial junctional complex. Myosin II and tropomyosin are
also found in the terminal web, which may explain its contractile
activity.
Microvilli greatly increase the area of cell surface (up to 40 times),
particularly at sites of active absorption. In the small intestine, they have
a very thick cell coat or glycocalyx, which reflects the presence of integral membrane glycoproteins, including enzymes concerned with digestion
and absorption. Irregular microvilli, filopodia, are also found on the
surfaces of many types of cell, particularly free macrophages and fibro -
blasts, where they may be associated with phagocytosis and cell motil -
ity. For further reading on the cytoskeleton of microvilli, see Brown and
McKnight (2010).
Long and branching microvilli are called stereocilia, an early misno -
mer, as they are not motile and lack microtubules. An appropriate name
is stereovilli. They are found on cochlear and vestibular receptor cells,
where they act as sensory transducers, and also in the absorptive epi -
thelium of the epididymis.
Intercellular junctions
The basolateral region of the plasma membrane of epithelial cells estab -
lishes junctions with adjacent cells and with structural components of the extracellular matrix. Intercellular junctions are resilient and dynamic,
and prevent epithelial tissues from dissociating into their component
cells. In adults, the epidermis withstands imposed deformations because
of the interplay of two components of intercellular junctions, the junc -
tional cytoskeleton and cell adhesion molecules ( Fig. 1.19). The estab-
lishment and maintenance of cell polarity in an epithelial layer depends
on two circumferential apical belts, the tight junctions and the zonulae
adherentes, running in parallel to each other and associated with
F-actin. These two belts control epithelial permeability and determine
epithelial cell polarity. The apical cell domain resides above the belts;
the basolateral cell domain resides below the belts. Desmosomes
(maculae adherentes) are a third class of spot-like intercellular adhe -
sion. In contrast to tight junctions and the zonulae adherentes, desmo -
somes do not form belts and link instead to intermediate filaments. The
hemidesmosome, anchoring epithelial cells to the basal lamina, also
links to intermediate filaments. Gap junctions are unique: they provide
direct connection between adjacent cells and are not linked to the
cytoskeleton. Molecular aspects of cell adhesion molecules will be con-
sidered first and then integrated with the junctional cytoskeleton to
define specific structural and molecular aspects of different intercellular
junctions.
Cell adhesion molecules
Cell adhesion molecules are transmembrane or membrane-anchored
glycoproteins that bridge the intercellular space from the plasma mem-
brane to form adhesive contacts. There are a number of molecular
subgroups, which are broadly divisible on the basis of their dependence
on calcium for function. Calcium-dependent cell adhesion molecules
include cadherins and selectins. Calcium-independent cell adhesion
molecules include the immunoglobulin-like superfamily of cell adhe -
sion molecules (Ig-CAMs), including nectins, and integrins, the only cell adhesion molecules consisting of two subunits ( α and β subunits).
Calcium-dependent cell adhesion molecules:
cadherins and selectins
Cadherins are single-pass transmembrane glycoproteins, with five
heavily glycosylated calcium-binding external domains and an intra -
cellular catenin-binding cytoplasmic tail. Catenins are intracellular
proteins linking cadherins to F-actin in the belt-arranged zonula adhe -
rens. The extracellular segment of cadherins participates in Ca2+-depend-
ent homophilic trans-interactions in which a cadherin molecule on one
cell binds to an identical cadherin molecule on an adjacent cell. After
binding, cadherins cluster laterally ( cis-interaction) at cell–cell junc -
tions to form a zipper-like structure that stabilizes tight adhesion between cells.
Different cell types possess different members of the cadherin family,
e.g. N-cadherins in nervous tissue, E-cadherins in epithelia, and
P-cadherins in the placenta. Two further members of the cadherin
family are the desmogleins and the desmocollins. Cadherins are present
in macula adherens and desmosomes but not in tight junctions or
hemidesmosomes (see below). Alterations in the expression of cadher-
ins in the epidermis produce pathological conditions such as blisters
and ulcerations. See Brieher and Yap (2013) for further reading on
cadherins and their associated cytoskeleton.
As with cadherins, selectins are Ca
2+-dependent. In contrast to cad -
herins, selectins do not establish homophilic trans-interactions. Instead,
they bind to carbohydrates and belong to the group of lectins. Each
selectin has an extracellular carbohydrate recognition domain (CRD) with binding affinity to a specific oligosaccharide attached to a protein or lipid. The molecular configuration and binding affinity of the CRD to carbohydrate moieties is Ca
2+-dependent. Selectins participate in
the homing of leukocytes circulating in blood towards tissues by
Fig . 1 .18 Microvilli sectioned longitudinally in the striated border of an
intestinal absorptive cell in a human duodenal biopsy specimen . Actin
filaments fill the cores of the microvilli and insert into the apical
cytoplasm . A prominent glycocalyx (formed by the extracellular domains
of plasma membrane glycoproteins) is seen as a fuzzy coat at the tips of
and between microvilli; it includes enzymes concerned with the final
stages of digestion . (Courtesy of Dr Bart Wagner, Histopathology
Department, Sheffield Teaching Hospitals, UK .)
| 62 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
23.e1
CHaPTER 1
When arranged in a regular parallel series, as typified by the absorp -
tive surfaces of the epithelial enterocytes of the small intestine and the
proximal convoluted tubule of the nephron of the kidneys, microvilli acquire a fuzzy appearance like the bristles of a paintbrush (the designa -
tions brush border or striated border are used at the light microscope
level).
The cytoplasmic tail recruits proteins of the catenin complex:
β-catenin is the first to be recruited and the cadherin– β-catenin complex
rapidly recruits α-catenin; α-catenin binds directly to F-actin and coor -
dinates the activity of actin nucleating proteins and actin binding part -
ners (such as vinculin and α-actinin) to provide the dynamic forces to
modulate cell–cell adhesion; p120-catenin binds to the cytoplasmic tail
of cadherin and becomes a positive regulator of cadherin function. | 63 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
24 SECTION 1
loops, a transmembrane segment and a cytoplasmic tail. The nectins
and Necls consist of four and five members, respectively. These are
present in the belt-like tight junctions and zonula adherens.
The nectin–afadin complex initiates the formation of a zonula
adherens and after cell–cell contacts are formed between adjacent
cells, cadherins are recruited to these contact sites. Afadin and α-catenin
interact with one another and also with F-actin through adaptor
proteins.
Integrins mediate cell–extracellular matrix and cell–cell interactions,
and integrate extracellular signals with the cytoskeleton and cellular
signalling pathways. Because integrins can be activated by proteins
binding to their extracellular or their intracellular domains, they can
function in a bidirectional fashion by transmitting information
outside-in (cues from the extracellular environment) and inside-out
(cues from the intracellular environment) of the cell. The integrin
family of proteins consists of α subunits and β subunits forming trans-
membrane heterodimers. The amino-acid sequence arginine–glycine–aspartic acid, or RGD motif, on target ligands (such as fibronectin,
laminin and other extracellular matrix proteins) has binding affinity
to the extracellular binding head of integrins. For further reading on
integrins and their ligands properties, see Barczyk et al (2010).
The actin-binding protein talin binds the cytoplasmic domain of
integrin β subunit and activates integrins. Vinculin interacts with talin
and α-actinin cross-links two filaments of actin. Kindlins, named after
the gene mutated in Kindler’s syndrome, a skin blistering disease, inter -
act with talin to activate integrins.extravasation across the endothelium. For additional reading on the
significance and mechanism of homing, see Girard et al (2012).
Three major types of selectin include L-selectin (for lymphocytes),
E-selectin (for endothelial cells) and P-selectin (for platelets).
Calcium-independent cell adhesion molecules:
Ig-Cams, nectins and integrins
Ig-CAMs are cell-surface glycoproteins with an extracellular domain
characterized by a variable number of immunoglobulin-like loops. Most Ig-CAMs have a transmembrane domain; others are attached to
the cell surface by a glycophosphatidyl inositol (GPI) anchor. As in
cadherins, Ig-CAMs establish homophilic interactions contributing to
cell–cell adhesion, although in a Ca
2+-independent manner. The cyto-
plasmic tail of Ig-CAMs also interacts with cytoskeletal components
such as F-actin, ankyrins and spectrin. Ig-CAMs can directly or indirectly
bind growth factor receptors and control their internalization.
Different types are expressed in different tissues. Neural cell adhe -
sion molecules (N-CAMs) are found on a number of cell types but are
expressed widely by neural cells. Intercellular adhesion molecules (ICAMs) are expressed on vascular endothelial cells. Cell adhesion molecule binding is predominantly homophilic, although some use a heterophilic mechanism, e.g. vascular intercellular adhesion molecule (VCAM), which can bind to integrins.
Nectins and nectin-like molecules (Necls) are members of the
Ig-CAM superfamily (see Takai et al (2008) for further reading on
nectins and Necls). They have an extracellular domain with three Ig-like
Fig . 1 .19 Intercellular junctions: the apical junctional complex and other junctional specializations, illustrating the protein components of each junction
and of the basal lamina . An anastomotic network of contacts between adjacent cell membranes forms a tight occluding junction . Basal plasma
membrane is attached to a basal lamina at a hemidesmosome . In a gap junction, numerous channels (pores within connexons) are clustered to form a
plaque-like junctional region between adjacent plasma membranes . (A and C are transmission electron micrographs; B and D are freeze-fractured
preparations .) A, An apical junctional complex . B, A tight junction . C, A hemidesmosome . D, A gap junction . (B, Courtesy of Dr Andrew Kent, King’s
College London . D, Courtesy of Professor Dieter Hülser, University of Stuttgart . A,C, From human tissue, courtesy of Dr Bart Wagner, Histopathology
Department, Sheffield Teaching Hospitals, UK . Diagram modified from Kierszenbaum AL, Tres LL . 2012 . Histology and Cell Biology: An Introduction to
Pathology . 3rd ed, Philadelphia: Elsevier, Saunders; 2011 .)
S S
S SFibronectin
Type IV collagen
CollagensClaudin
Occludin
ZO-1, ZO-2 and ZO-3 Afadin–nectin complex
Plakoglobin, plakophilin
and desmoplakinAfadin–nectin complex
Cadherins
Cadherins
Integrin
Integrin
LamininSelectinsIg-CAMs Catenin complex
Actin
Actin Talin
VinculinIntermediate
filaments
Intermediate filaments
Nidogen (entactin) PerlecanTight (occluding) junctionTight (occluding) junction
Tight (occluding) junction Zonula adherens
Macula adherens
HemidesmosomeGap
junctionZonula adherens
Macula
adherensAPICAL DOMAIN BASOLATERAL DOMAIN BASAL LAMINA
APICAL JUNCTIONAL COMPLEXA
C DB
Gap junction Hemidesmosome | 64 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
24.e1
CHaPTER 1
Homing, a process that also enables thymus-derived T cells (see
Ch. 4) to home in on lymph nodes, consists of two phases. In the first,
selectin phase, carbohydrate ligands on the surface of leukocytes adhere
loosely to selectins present on the surface of endothelial cells. During
the second, cooperative sequential integrin phase, strong adhesion
permits the transendothelial migration of leukocytes into the extravas -
cular space in cooperation with cell adhesion molecules of the Ig-CAM superfamily.
Nectins can interact homophilically or heterophilically with other
nectins to mediate, primarily, adhesion. The intracellular domain of
nectins binds to the cytoplasmic adaptor protein afadin, which links to
actin, whereas Necls interact with scaffolding proteins but not to afadin.
Necls are involved in a large variety of cellular functions, including
axon–glial interaction, Schwann cell differentiation and myelination.
In humans there are about 18 α-subunit subtypes and 8 β-subunit
subtypes, which produce 24 integrin heterodimers. The subunits are
associated by non-covalent interactions and consist of an extracellular
ligand-binding head, two multidomain segments, two single-pass trans-
membrane segments and two cytoplasmic tails. Upon binding of extra-
cellular ligands, integrins undergo a conformational change (integrin
activation), which allows the recruitment of several cytoplasmic F-actin
activator proteins (such as talin, vinculin, α-actinin and kindlins) to
their short cytoplasmic domain. This results in the formation of a protein complex that interacts with the actin cytoskeleton.
In addition, the protein complex promotes the recruitment and
activation of several protein kinases (such as focal adhesion kinase),
leading to the activation of signalling pathways essential for several
cellular activities such as cell migration, proliferation, survival and gene
expression. | 65 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
ageing, cellular senescence, cancer and apoptosis
25
CHaPTER 1
smooth muscle cells, in the intercalated discs of cardiac muscle cells
and between glial cells and neurones. The junctions involve cadherins
attached indirectly to actin filaments on the inner side of the
membrane.
Desmosomes (maculae adherentes)
Desmosomes are limited, plaque-like areas of particularly strong inter -
cellular contact. In epithelial cells, they may be located subjacent to the tight junction and zonula adherens belts, forming collectively the epi -
thelial apical junctional complex (see Fig. 1.19A). The intercellular gap
is approximately 25 nm; it is filled with electron-dense filamentous
material (the intercellular cadherins) running transversely across it and
is also marked by a series of densely staining bands (the cytoplasmic
dense plaques) running parallel to the cell surfaces. Adhesion is medi -
ated by Ca2+-dependent cadherins, desmogleins and desmocollins.
Within the cells on either side, each cytoplasmic dense plaque underlies the plasma membrane and consists of the proteins plakophilin, desmo-
plakin and plakoglobin ( γ-catenin), into which the ends of intermedi -
ate filaments are inserted. The type of intermediate filament depends on the cell type, e.g. keratins are found in epithelia and desmin fila -
ments are found in cardiac muscle cells. Desmosomes form strong anchorage points, likened to spot-welds, between cells subject to
mechanical stress, e.g. in the prickle cell layer of the epidermis, where
they are extremely numerous and large.
Hemidesmosomes
Hemidesmosomes are asymmetric anchoring junctions found between the basal side of epithelial cells and the associated basal lamina.
The latter is a component of the basement membrane and contains laminin, an integrin ligand. The other component of the basement
membrane is the reticular lamina, a collagen-containing layer produced
by fibroblasts that also contains fibronectin, another integrin ligand.
Hemidesmosomes resemble a single-sided desmosome, anchored on
one side to the plasma membrane, and on the other to the basal lamina
and adjacent collagen fibrils ( Fig. 1.19C). The plaque has distinct pro -
teins not seen in the plaques of a zonula adherens or a macula adher -
ens: BPAG1 (bullous pemphigoid antigen 1), a member of the plakin
family, and BPAG2 (bullous pemphigoid antigen 2), which possesses
an extracellular collagenous domain. BPAG1 and BPAG2 were initially
detected in patients with bullous pemphigoid, an autoimmune blister-
ing disease. On the cytoplasmic side of the dense plaque there is a less
dense plate into which keratin filaments are inserted, where they inter -
act with the protein plectin associated with integrin α6β4. Hemidesmo-
somes use integrins and anchoring filaments (laminin 5) as their
adhesion molecules anchored to the basal lamina, whereas desmo -
somes use cadherins.
Focal adhesion plaques
Less highly structured attachments with a similar arrangement exist
between many other cell types and their surrounding matrices, e.g.
between smooth muscle cells and their matrix fibrils, and between the
ends of skeletal muscle cells and tendon fibres. The smaller, punctate
adhesions resemble focal adhesion plaques, which are regions of local
attachment between cells and the extracellular matrix. They are typically
situated at or near the ends of actin filament bundles (stress fibres),
anchored through intermediary proteins to the cytoplasmic domains of
integrins. In turn, these are attached at their external ends to collagen
or other filamentous structures in the extracellular matrix. They are
usually short-lived; their formation and subsequent disruption are part
of the motile behaviour of migratory cells. See Geiger et al (2009) for
further reading on focal adhesions.
Gap junctions (communicating junctions)
Gap junctions resemble tight junctions in transverse section, but the
two apposed lipid bilayers are separated by an apparent gap of 3 nm,
which is bridged by a cluster of transmembrane channels (connexons).
Each connexon is formed by a ring of six connexin proteins whose
external surfaces meet those of the adjacent cell in the middle. A minute
central pore links one cell to the next (Fig. 1.19D). Larger assemblies
of many thousands of channels are often packed in hexagonal arrays.
Gap junctions occur between numerous cells, including hepatocytes
and cardiac myocytes.
AGEING, CELLULAR SENESCENCE, CANCER
AND APOPTOSIS
Ageing is a universal feature of biological organisms, defined by a
gradual decline over time in cell and tissue function that often, but not
Genetic mutations in integrins or integrin regulators have been asso -
ciated with Glanzmann’s thrombasthenia (caused by mutations in
integrin β3 subunit), the immunodeficiency disorder leukocyte adhe -
sion deficiency types I and III (determined by mutations in integrin β2
subunit and kindlin 3, respectively) and skin diseases (caused by muta -
tions in kindlin 1 and integrin α2, α6 and β3 subunits). Integrins are
essential in the homing process, following the selectin phase, and are
also involved in tumour progression and metastasis.
Specialized intercellular junctions
Specialized cell–cell junctions are the hallmark of all epithelial tissues. There are two major categories: symmetric junctions and asymmetric
junctions. Symmetric junctions may be subdivided into three types:
tight junctions (also known as occluding junctions or zonulae occlu -
dentes); anchoring junctions (including zonulae adherentes, or belt desmosomes, and maculae adherentes, or spot desmosomes); and com -
munication junctions, represented by gap junctions. Tight junctions and anchoring junctions are components of the epithelial apical junctional
complex. Hemidesmosomes are asymmetric junctions (see Fig. 1.19).
Tight junctions (occluding junctions,
zonulae occludentes)
Tight junctions are the most apical component of the epithelial apical
junctional complex. The main functions of tight junctions are the regu -
lation of the paracellular permeability of the epithelial layer and the formation of an apical–basolateral intramembrane diffusion barrier,
the hallmark of epithelial cell polarity. Tight junctions form a continu -
ous belt (zonula) around the cell perimeter, near the apical domain of epithelial cells, and are connected to the actin cytoskeleton. At the site
of the tight junction, the plasma membranes of adjacent cells come into
close contact, so that the space between them is obliterated. Freeze-
fracture electron microscopy shows that the contact between these
membranes is represented by branching and anastomosing sealing
strands of protein particles on the P (protoplasmic) face of the lipid
bilayer (Fig. 1.19A,B). A tight junction contains numerous proteins:
occludins and claudins, members of the tetraspanin family of proteins,
containing four transmembrane domains, two loops and two cytoplas -
mic tails – occludins and tetraspanins provide the molecular basis for the formation of the branching and anastomosing strands seen in
freeze-fracture preparations; the afadin–nectin complex and junctional
adhesion molecules (JAMs), each forming cis-homodimers and interact -
ing with each other through their extracellular domains (forming trans-
homodimers) – nectins and JAMs are members of the immunoglobulin
superfamily, and the afadin component of the afadin–nectin complex
interacts with F-actin; and cytosolic zonula occludens proteins 1, 2 and
3 (ZO-1, ZO-2 and ZO-3). ZO-1 protein is associated with afadin and
the intracellular domain of JAMs. All three ZO proteins facilitate the
reciprocal interaction of occludins, claudins and JAMs with F-actin.
Defects in paracellular magnesium permeability and reabsorption in
kidneys occur when there is a mutation in claudin 16 and claudin 19
(renal magnesium wasting). For further reading on claudins, see
Escudero-Esparza et al (201 1). For further reading on JAMs, see Bazzoni
(2003).
anchoring junctions
In contrast to tight junctions, zonulae adherentes and maculae adher -
entes are characterized by the presence, along the cytosolic sides of the plasma membranes of adjacent epithelial cells, of symmetric dense
plaques connected to each other across the intercellular space by cad -
herins. They differ in that F-actin is associated with plaques in zonulae adherentes and intermediate filaments are linked to plaques in maculae
adherentes.
Zonula adherens (belt desmosome)
A zonula adherens is a continuous belt-like zone of adhesion parallel
and just basal to a tight junction and also encircling the apical perimeter
of epithelial cells. Ca2+-dependent cell adhesion molecules (members
of the desmoglein and desmocollin families of cadherins) are key com -
ponents of a zonula adherens. In addition to the cadherin–catenin
complex, a zonula adherens also houses the afadin–nectin complex.
A specific component of a zonula adherens is a cytoplasmic dense
plaque attached to the cytosolic side of the plasma membrane. It con -
sists of desmoplakin, plakophilin and plakoglobin proteins (the latter
is also known as γ-catenin). A similar plaque is seen in a macula adhe -
rens or spot desmosome (see below).
Fascia adherens
A fascia adherens is similar to a zonula adherens, but is more
limited in extent and forms a strip or patch of adhesion, e.g. between
| 66 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
25.e1
CHaPTER 1
Essentially, two molecules, cadherins and afadin, link to the actin
cytoskeleton. In cultured cells, nectins appear to initiate the formation
of a zonula adherens before the involvement of cadherins. | 67 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
BaSIC STR uCTuRE aNd fu NCTION Of CEllS
26 SECTION 1
enter the cell. The intrinsic mitochondrial route involves the release of
cytochrome c from the space between the inner and outer mitochon -
drial membranes into the cytosol. Extrinsic and intrinsic pathways
work cooperatively in the subsequent activation of a family of initiator-
effector proteases, known as caspases (cysteine aspartic acid-specific
proteases), which are present in healthy cells as inactive precursor
enzymes or zymogens. Activation of caspases 3, 6 and 7 mediates apop -
tosis by initiating a cascade of degradative processes that target major constituents of the cell cytoskeleton, producing membrane blebbing, a
distinctive feature of apoptosis caused by cytosolic and nuclear frag -
ments flowing into the developing apoptotic bodies. Caspase cleavage inactivates many systems that normally promote damage repair and
support cell viability, and activates a number of proteins that promote
the death and disassembly of the cell. For further reading on apoptosis,
see Taylor et al (2008).always, decreases the longevity of an individual. The hallmarks of
ageing are reviewed in López-Otín et al (2013).
Cellular senescence is defined by an irreversible arrest in cell prolif -
eration when cells experience DNA damage at telomeres and a decrease in mitogenic signalling. In contrast to reversibly arrested quiescent cells
in G
0 of the cell cycle, senescent growth arrest is irreversible; cells in this
state cannot be stimulated to proliferate by known stimuli and cannot
be prompted to re-enter the cell cycle by physiological mechanisms. For
further reading on senescence and the cell cycle, see Chandler and Peters
(2013). Senescent cells can cause or foster degenerative diseases. In old age, cellular senescence in humans determines typical pathologies, in -
cluding atherosclerosis leading to stroke, osteoporosis, macular degen -
eration, cardiopulmonary and renal failure, and neurodegenerative
diseases such as Alzheimer’s and Parkinson’s disease.
Senescent cells undergo changes in gene expression, which result in
the secretion of proinflammatory cytokines, growth factors and pro -
teases, activities that collectively define a senescence-associated secre -
tory phenotype capable of triggering angiogenesis, inflammatory
responses, stem cell renewal and differentiation, and which may also
determine resistance to cancer chemotherapy. Senescent cells can be
identified histochemically by their expression of either senescence-
associated β-galactosidase, a lysosomal marker which is overexpressed
in these cells, or the tumour suppressor protein p16
INK4a, which pro-
motes the formation of senescence-associated chromatin. For further reading on ageing, cellular senescence and cancer, see Campisi (2013).
Cellular senescence can be caused by a disruption of metabolic
signalling pathways, derived from mitogens and proliferation factors,
and the activation of tumour suppressors, combined with telomere
shortening and genomic damage. See Sahin and DePinho (2012) for
further reading.
Cellular senescence suppresses tumorigenesis because cell prolifera -
tion is required for cancer development. However, senescent cells can stimulate the proliferation and malignant progression of adjacent pre -
malignant cells by the release of senescence-inducing oncogenic stimuli. Cancer cells must harbour mutations to prevent telomere-dependent
and oncogene-induced senescence, such as in the p53 and p16-
retinoblastoma protein pathways. See López-Otín et al (2013) for
further reading on the pathogenesis of ageing.
Apoptosis
Cells die as a result of either tissue injury (necrosis) or the internal activation of a ‘suicide’ programme (apoptosis) in response to extrinsic
or intrinsic cues. Apoptosis (programmed cell death) is defined by the
controlled demolition of cellular constituents and the ultimate uptake
of apoptotic cell fragments by other cells to prevent immune responses.
Some senescent cells become resistant to cell-death signalling, i.e. they
are apoptosis-resistant. In effect, senescence blocks growth of damaged
or stressed cells, whereas apoptosis quickly disposes of them. Apoptosis
is a central mechanism controlling multicellular development. During
morphogenesis, apoptosis mediates activities such as the separation of
the developing digits, and plays an important role in regulating the
number of neurones in the nervous system (the majority of neurones
die during development). Apoptosis also ensures that inappropriate
or inefficient T cells are eliminated in the thymus during clonal selection.
The morphological changes exhibited by necrotic cells are very dif -
ferent from those seen in apoptotic cells. Necrotic cells swell and sub -
sequently rupture, and the resulting debris may induce an inflammatory response. Apoptotic cells shrink, their nuclei and chromosomes frag -
ment, forming apoptotic bodies, and their plasma membranes undergo conformational changes that act as a signal to local phagocytes. The
dead cells are removed rapidly, and as their intracellular contents are
not released into the extracellular environment, inflammatory reactions
are avoided; the apoptotic fragments also stimulate macrophages to
release anti-inflammatory cytokines.
Apoptosis and cell proliferation are intimately coupled; several cell
cycle regulators can influence both cell division and apoptosis. The
signals that trigger apoptosis include withdrawal of survival factors or
exposure to inappropriate proliferative stimuli. Three main routes to
the induction of apoptosis have been established ( Fig. 1.20). Two, the
Fas ligand (FasL) pathway and the granzyme B pathway, are extrinsic,
whereas the mitochondrial route is intrinsic. The Fas ligand (FasL) pathway involves binding of FasL to death receptors on the plasma membrane and recruitment of adaptor proteins, such as the Fas-associ -
ated death domain proteins, followed by the recruitment and activation of caspase 8. The granzyme B pathway involves creation of a perforin plasma membrane channel enabling the caspase-like granzyme B to Fig . 1 .20 Caspase activation pathways during apoptosis . A, The
granzyme B extrinsic pathway activates caspase 8 and caspase 3
following entry of granzyme B across the plasma membrane pore-forming
protein, perforin . This pathway is observed in cytotoxic T cells or natural
killer cells for delivery of the protease granzyme B to target cells . B, The
Fas ligand (FasL) extrinsic pathway is initiated by binding of FasL to clustered transmembrane death receptors that recruit adaptor proteins, such as the Fas-associated death-domain protein (FADD) to their
intracellular domain, which in turn recruits and aggregates caspase 8
molecules, which become activated . Activated caspase 8 activates
caspase 7 and caspase 3 . C, The cytochrome c intrinsic pathway starts
when granzyme B or activated caspase 8 causes the truncation by proteolysis of the protein BIDD (BH3-interacting domain death agonist),
which penetrates a mitochondrion through BAX–BAK (BCL-2 associated
X protein–BCL-2 antagonist killer) channel proteins on the outer mitochondrial membrane, causing the release of cytochrome c.
Cytochrome c enables the assembly of the apoptosome (consisting of
seven molecules of apoptosis protease-activating factor-1 (APAF1) and
seven molecules of caspase 9), which in turn activates caspase 3 and
caspase 7 . Finally, the proteolytic activation cascade of caspase 6,
caspase 2, caspase 8 and caspase 10 executes cell deconstruction . Fas ligand
Granzyme B
Granzyme BPerforinDeath receptors
FADD
BIDDCaspase 8
Caspase 3Cytochrome c pathway CGranzyme B pathwayA FasL pathwayB
Caspase 9ApoptosomeMitochondrion
Cytochrome c
Caspase 7Active caspase 8
Caspase 3
Caspase 2
Caspase 10Caspase 6
Caspase 8BAX–BAK
channels
Video 1 .1 Mitosis in a cell with fluorescently-labelled chromosomes
and microtubules . Bonus e-book video
| 68 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
26.e1
CHaPTER 1
The ends of the chromosomes, or telomeres, become shorter and
more dysfunctional with each DNA replication round. Telomere short -
ening has been shown to activate DNA damage responses, leading to
mitochondrial dysfunction (a decrease in production of ATP and an increase in reactive oxygen species) and the activation of p53, which
induces growth arrest, apoptosis and senescence of stem cells and pro -
genitor cells. p53 interconnects with different longevity metabolic sig -
nalling pathways, including the insulin, insulin-like growth factor I
(IGFI) and mammalian target of rapamycin (mTOR) pathways, which are known to regulate lifespan by increasing the expression of genes involved in stress resistance and energy balance. Mutations in TERC (the RNA component of telomerase) and TERT (the catalytic component of telomerase) are found in patients with the premature ageing syndrome,
dyskeratosis congenita (poor growth of fingernails and toenails, skin
pigmentation and oral leukoplakia). Other important contributors to cell senescence are dysregulated autophagy and lack of disposal of misfolded proteins by the ubiquitin–26S proteasome machinery.
These responses are collectively designated telomere-initiated cellular senescence. | 69 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
27
CHaPTER 1Key references
KEY REFERENCES
Bray D 2001 Cell Movements. New York: Garland.
A comprehensive presentation of the structural and molecular features of the
cytoskeleton, including its properties and behaviour in cell and organelle movement in living cells.
Burke B, Stewart CL 2013 The nuclear lamins: flexibility in function. Nat Rev
Mol Cell Biol 14:13–24.
An up-to-date, detailed description of the nuclear lamina and its major
components, lamins, members of the intermediate filament protein family.
Chinnery PF, Hudson G 2013 Mitochondrial genetics. Br Med Bull 106:
135–59.
A detailed survey of the involvement of mitochondrial DNA (mtDNA) defects in human disease, with a specific focus on the mechanisms controlling mtDNA inheritance.
Girard JP, Moussion C, Förster R 2012 HEVs, lymphatics and homeostatic
immune cell trafficking in lymph nodes. Nat Rev Immunol 12:
762–73.A comprehensive description of the continuous trafficking of immune cells across the vascular endothelium (homing) engaging cell adhesion molecules.
Kierszenbaum AL, Tres LL 2012 Histology and Cell Biology: An Introduction
to Pathology. Philadelphia: Elsevier, Saunders.
An integrated visual view of histology, cell biology and basic pathology
focused on structure and function, including human pathological examples
from a molecular viewpoint.
López-Otín C, Blasco MA, Partridge L et al 2013 The hallmarks of aging. Cell
153:1 194–217.A review of recent advances in the pathogenesis of ageing, defined by a
gradual loss of physiological integrity leading to major human pathological conditions. Genomic instability, telomerase attrition, epigenetic alterations, loss of proteolysis and mitochondrial dysfunction are considered.
Pollard TD, Earnshaw WC 2008 Cell Biology. Philadelphia: Elsevier,
Saunders.
A detailed and comprehensive account of structural and molecular aspects of
cell biology, including abnormalities related to human disease.
Porter RM, Lane EB 2003 Phenotypes, genotypes and their contribution to
understanding keratin function. Trends Genet 19:278–85.
A correlation of human epithelial pathological conditions with mouse mutant studies focused on keratin diversity required for cells to attune to mechanical and biochemical signalling.
Saftig P, Klumperman J 2009 Lysosome biogenesis and lysosomal mem -
brane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10:
623–35.The participation of lysosomes in the degradation of extracellular material internalized by endocytosis and lysosomal sorting pathways, reviewed within the context of human diseases resulting from defective lysosomal biogenesis.
Scholey JM 2008 Intraflagellar transport motors in cilia: moving along the
cell’s antenna. J Cell Biol 180:23–9.
Ciliopathies derived from the defective assembly, maintenance and function
of the axoneme in motile and sensory cilia, considered within the framework
of intraflagellar transport proteins and associated molecular motors. | 70 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Basic structure and function of cells
27.e1
CHaPTER 1
REFERENCES
Baldari CT, Rosenbaum J 2010 Intraflagellar transport: it’s not just for cilia
anymore. Curr Opin Cell Biol 22:75–80.
Barczyk M, Carracedo S, Gullberg D 2010 Integrins. Cell Tissue Res
339:269–80.
Bazzoni G 2003 The JAM family of junctional adhesion molecules. Curr
Opin Cell Biol 15:525–30.
Boisvert FM, van Koningsbruggen S, Navascués J et al 2007 The multifunc-
tional nucleolus. Nat Rev Mol Cell Biol 8:574–85.
Boya P, Reggiori F, Codogno P 2013 Emerging regulation and functions of
autophagy. Nat Cell Biol 15:713–20.
Braverman NE, D’Agostino MD, Maclean GE 2013 Peroxisome biogenesis
disorders: biological, clinical and pathophysiological perspectives. Dev
Disabil Res Rev 17:187–96.
Bravo R, Parra V, Gatica D et al 2013 Endoplasmic reticulum and the
unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol 301:215–90.
Bray D 2001 Cell Movements. New York: Garland.
A comprehensive presentation of the structural and molecular features of the
cytoskeleton, including its properties and behaviour in cell and organelle
movement in living cells.
Brieher WM, Yap AS 2013 Cadherin junctions and their cytoskeleton(s).
Curr Opin Cell Biol 25:39–46.
Briscoe J, Thérond PP 2013 The mechanisms of Hedgehog signalling and its
roles in development and disease. Nat Rev Mol Cell Biol 14:418–31.
Brown JW, McKnight CJ 2010 Molecular model of the microvillar cytoskel -
eton and organization of the brush border. PLoS One 5:e9406.
Burke B, Stewart CL 2013 The nuclear lamins: flexibility in function. Nat Rev
Mol Cell Biol 14:13–24.An up-to-date, detailed description of the nuclear lamina and its major components, lamins, members of the intermediate filament protein family.
Campisi J 2013 Aging, cellular senescence and cancer. Annu Rev Physiol
75:685–705.
Chandler H, Peters G 2013 Stressing the cell cycle in senescence and aging.
Curr Op Cell Biol Dec; 25:765–71.
Chinnery PF, Hudson G 2013 Mitochondrial genetics. Br Med Bull
106:135–59.A detailed survey of the involvement of mitochondrial DNA (mtDNA) defects in human disease, with a specific focus on the mechanisms controlling mtDNA inheritance.
Clarke PR, Zhang C 2008 Spatial and temporal coordination of mitosis by
Ran GTPase. Nat Rev Mol Cell Biol 9:464–77.
Dominguez R 2010 Structural insights into de novo actin polymerization.
Curr Opin Struct Biol 20:217–25.
Escudero-Esparza A, Jiang WG, Martin TA 201 1 The Claudin family and its
role in cancer and metastasis. Front Biosci 16:1069–83.
Geiger B, Spatz JP, Bershadsky AD 2009 Environmental sensing through
focal adhesions. Nat Rev Mol Cell Biol 10:21–33.
Girard JP, Moussion C, Förster R 2012 HEVs, lymphatics and homeostatic
immune cell trafficking in lymph nodes. Nat Rev Immunol 12:762–73.A comprehensive description of the continuous trafficking of immune cells across the vascular endothelium (homing) engaging cell adhesion molecules.
Gönczy P 2012 Towards a molecular architecture of centriole assembly. Nat
Rev Mol Cell Biol 13:425–35.
Hammer JA 3rd, Sellers JR 2012 Walking to work: roles for class V myosins
as cargo transporters. Nat Rev Mol Cell Biol 13:13–26.
Hao L, Scholey JM 2009 Intraflagellar transport at a glance. J Cell Sci
122:889–92.
Herrmann H, Bär H, Kreplak L et al 2007 Intermediate filaments: from cell
architecture to nanomechanics. Nat Rev Mol Cell Biol 8:562–73.
Jin H, Nachury MV 2009 The BBSome. Curr Biol 19:R472–3.
Kierszenbaum AL, Rivkin E, Tres LL 201 1 Cytoskeletal track selection during
cargo transport in spermatids is relevant to male fertility. Spermatogen -
esis 1:221–30.
Kierszenbaum AL, Tres LL 2012 Histology and Cell Biology: An Introduction
to Pathology. Philadelphia: Elsevier, Saunders.
An integrated visual view of histology, cell biology and basic pathology focused on structure and function, including human pathological examples from a molecular viewpoint.
López-Otín C, Blasco MA, Partridge L et al 2013 The hallmarks of aging. Cell
153:1 194–217.A review of recent advances in the pathogenesis of ageing, defined by a gradual loss of physiological integrity leading to major human pathological conditions. Genomic instability, telomerase attrition, epigenetic alterations, loss of proteolysis and mitochondrial dysfunction are considered.
Luger K, Dechassa ML, Tremethick DJ 2012 New insights into nucleosome
and chromatin structure: an ordered state or a disordered affair? Nat Rev Mol Cell Biol 13:436–47.
Mostowy S, Cossart P 2012 Septins: the fourth component of the cytoskel -
eton. Nat Rev Mol Cell Biol 13:183–94.
Muller PA, Vousden KH 2013 p53 mutations in cancer. Nat Cell Biol
15:2–8.
Munro S 201 1 The golgin coiled-coil proteins of the Golgi apparatus. Cold
Spring Harb Perspect Biol 3:a005256.
Nandakumar J, Cech TR 2013 Finding the end: recruitment of telomerase
to telomeres. Nat Rev Mol Cell Biol 14:69–82.
Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
intermediate filaments in normal and diseased epithelia. Curr Op Cell
Biol 25:1–10.
Park C, Cuervo AM 2013 Selective autophagy: talking with the UPS. Cell
Biochem Biophys 67:3–13.
Pollard TD, Earnshaw WC 2008 Cell Biology. Philadelphia: Elsevier,
Saunders.
A detailed and comprehensive account of structural and molecular aspects of cell biology, including abnormalities related to human disease.
Porter RM, Lane EB 2003 Phenotypes, genotypes and their contribution to
understanding keratin function. Trends Genet 19:278–85.A correlation of human epithelial pathological conditions with mouse mutant studies focused on keratin diversity required for cells to attune to mechanical and biochemical signalling.
Raices M, D’Angelo MA 2012 Nuclear pore complex composition: a new
regulator of tissue-specific and developmental functions. Nat Rev Mol Cell Biol 13:687–99.
Rotty JD, Wu C, Bear JE 2013 New insights into the regulation and cellular
functions of the ARP2/3 complex. Nat Rev Mol Cell Biol 14:7–12.
Saftig P, Klumperman J 2009 Lysosome biogenesis and lysosomal mem -
brane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10:623–35.The participation of lysosomes in the degradation of extracellular material internalized by endocytosis and lysosomal sorting pathways, reviewed within the context of human diseases resulting from defective lysosomal biogenesis.
Sahin E, DePinho RA 2012 Axis of ageing: telomeres, p53 and mitochondria.
Nat Rev Mol Cell Biol 13:397–404.
Scholey JM 2008 Intraflagellar transport motors in cilia: moving along the
cell’s antenna. J Cell Biol 180:23–9.Ciliopathies derived from the defective assembly, maintenance and function of the axoneme in motile and sensory cilia, considered within the framework of intraflagellar transport proteins and associated molecular motors.
Settembre C, Fraldi A, Medina DL et al 2013 Signals from the lysosome:
a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14:283–96.
Simon DN, Wilson KL 201 1 The nucleoskeleton as a genome-associated
dynamic ‘network of networks’ . Nat Rev Mol Cell Biol 12:695–708.
Smith CE, Ordovás JM 2012 Update on perilipin polymorphisms and
obesity. Nutr Rev 70:61 1–21.
Spang A 2013 Traffic COPs: rules of detection. The EMBO J 32:915–16.
Takai Y, Miyoshi J, Ikeda W et al 2008 Nectins and nectin-like molecules:
roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol 9:603–15.
Taylor RC, Cullen SP, Martin SJ 2008 Apoptosis: controlled demolition at
the cellular level. Nat Rev Mol Cell Biol 9:231–41.
Theodoulou FL, Bernhardt K, Linka N et al 2013 Peroxisome membrane
proteins: multiple trafficking routes and multiple functions? Biochem J 451:345–52.
Tomko RJ Jr, Hochstrasser M 2013 Molecular architecture and assembly of
the eukaryotic proteasome. Annu Rev Biochem 82:415–45.
Tres LL 2005 XY chromosomal bivalent: nucleolar attraction. Mol Reprod
Dev 72:1–6.
Weinbaum S, Tarbell JM, Damiano ER 2007 The structure and function of
the endothelial cell glycocalyx layer. Annu Rev Biomed Eng 9:121–67.
Worman HJ 2012 Nuclear lamins and laminopathies. J Pathol 226:316–25. | 71 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
28 SECTION 1
CHAPTER 2 Integrating cells into tissues
basal lamina, which is synthesized predominantly by the epithelial
cells. The basal lamina is described on page 34.
Epithelia can usually regenerate when injured. Indeed, many epithe -
lia continuously replace their cells to offset cell loss caused by mechani -
cal abrasion (reviewed in Blanpain et al (2007)). Blood vessels do not
penetrate typical epithelia and so cells receive their nutrition by diffu -
sion from capillaries of neighbouring connective tissues. This arrange -
ment limits the maximum thickness of living epithelial cell layers. Epithelia, together with their supporting connective tissue, can often be
removed surgically as one layer, which is collectively known as a mem -
brane. Where the surface of a membrane is moistened by mucous glands it is called a mucous membrane or mucosa, whereas a similar
layer of connective tissue covered by mesothelium is called a serous
membrane or serosa.
CLASSIFICATION
Epithelia can be classified as unilaminar (single-layered, simple), in
which a single layer of cells rests on a basal lamina; or multilaminar,
in which the layer is more than one cell thick. The latter includes:
stratified squamous epithelia, in which flattened superficial cells are constantly replaced from the basal layers; urothelium (transitional epi -
thelium), which serves special functions in the urinary tract; and other multilaminar epithelia such as those lining the largest ducts of some
exocrine glands, which, like urothelium, are replaced only very slowly
under normal conditions. Seminiferous epithelium is a specialized
multilaminar tissue found only in the testis.
Unilaminar (simple) epithelia
Unilaminar epithelia are further classified according to the shape of their cells, into squamous, cuboidal, columnar and pseudostratified
types. Cell shape may, in some cases, be related to cell volume. Where
little cytoplasm is present, there are generally few organelles and there -
fore there is low metabolic activity and cells are squamous or low cuboidal. Highly active cells, e.g. secretory epithelia, contain abundant
mitochondria and endoplasmic reticulum, and are typically tall cuboi -
dal or columnar. Unilaminar epithelia can also be subdivided into those that have special functions, such as those with cilia, numerous
microvilli, secretory vacuoles (in mucous and serous glandular cells) or
sensory features. Myoepithelial cells, which are contractile, are found as
isolated cells associated with glandular structures, e.g. salivary and
mammary glands.
Squamous epithelium
Simple squamous epithelium is composed of flattened, tightly apposed,
polygonal cells (squames). This type of epithelium is described as tes -
sellated when the cells have complex, interlocking borders rather than
straight boundaries. The cytoplasm may in places be only 0.1 µm thick
and the nucleus usually bulges into the overlying space (Fig. 2.2A).
These cells line the alveoli of the lungs, where their surface area is huge
and cytoplasmic volume correspondingly large, and they also form the
outer capsular wall of renal corpuscles, the thin segments of the renal
tubules and various parts of the inner ear. Because it is so thin, simple
squamous epithelium allows rapid diffusion of gases and water across
its surface; it may also engage in active transport, as indicated by the
presence of numerous endocytic vesicles in these cells. Tight junctions
(occluding junctions, zonulae adherentes) between adjacent cells
ensure that materials pass primarily through cells, rather than between them.
Cuboidal and columnar epithelia
Cuboidal and columnar epithelia consist of regular rows of cylindrical cells (Figs 2.2B, C). Cuboidal cells are approximately square in vertical section, whereas columnar cells are taller than their diameter, and both Cells evolved as single, free-living organisms, but natural selection
favoured more complex communities of cells, multicellular organisms,
where groups of cells specialize during development to carry out specific
functions for the body as a whole. This allowed the emergence of larger
organisms with greater control over their internal environment and the
evolution of highly specialized organic structures such as the brain.
The human body contains more than 200 different cell types, sharing the same genome but with different patterns of gene expression.
Some cells in the body are essentially migratory, but most exist as
cellular aggregates in which individual cells carry out similar or closely
related functions in a coordinated manner. These aggregates are termed
tissues, and can be classified into a fairly small number of broad catego -
ries on the basis of their structure, function and molecular properties. On the basis of their structure, most tissues are divided into four major
types: epithelia, connective or supporting tissue, muscle and nervous
tissue. Epithelia are continuous layers of cells with little intercellular
space, which cover or line surfaces, or have been so derived. In connec-
tive tissues, the cells are embedded in an extracellular matrix, which,
typically, forms a substantial and important component of the tissue.
Muscle consists largely of specialized contractile cells. Nervous tissue
consists of cells specialized for conducting and transmitting electrical
and chemical signals and the cells that support this activity.
There is molecular evidence that this structure-based scheme of clas -
sification has validity. Thus the intermediate filament proteins charac -
teristic of all epithelia are keratins (Pan et al 2012); those of connective
tissue are vimentins; those of muscle are desmins; and those of nervous tissue are neurofilament and glial fibrillary acidic proteins. However,
cells such as myofibroblasts, neuroepithelial sensory receptors and
ependymal cells of the central nervous system have features of more
than one tissue type. Despite its anomalies, the scheme is useful for
descriptive purposes; it is widely used and will be adopted here.
In this chapter, two of the major tissue categories, epithelia and
general connective and supporting tissues, will be described. Special -
ized skeletal connective tissues, i.e. cartilage and bone, together with skeletal muscle, are described in detail in Chapter 5 as part of the mus -
culoskeletal system overview. Smooth muscle and cardiac muscle are described in Chapter 6. Nervous system tissues are described in Chapter
3. Specialized defensive cells, which also form a migrant population within the general connective tissues, are considered in more detail in
Chapter 4, with blood, lymphoid tissues and haemopoiesis.
EPITHELIA
The term epithelium is applied to the layer or layers of cells that cover the body surfaces or line the body cavities that open on to it. The fate
of embryonic epithelial populations is illustrated in Figure 12.3. Epi -
thelia function generally as selective barriers that facilitate, or inhibit, the passage of substances across the surfaces they cover. In addition,
they may: protect underlying tissues against dehydration, chemical or
mechanical damage; synthesize and secrete products into the spaces
that they line; and function as sensory surfaces. In this respect, many
features of nervous tissue can be regarded as those of a modified
epithelium and the two tissue types share an origin in embryonic ectoderm.
Epithelia (Fig. 2.1) are predominantly cellular and the little extracel -
lular material they possess is limited to the basal lamina. Intercellular
junctions, which are usually numerous, maintain the mechanical cohe -
siveness of the epithelial sheet and contribute to its barrier functions.
A series of three intercellular junctions forms a typical epithelial junc -
tional complex: in sequence from the apical surface, this consists of a tight junctional zone, an adherent (intermediate) junctional zone and a region of discrete desmosome junctions. Epithelial cell shape is most usually polygonal and partly determined by cytoplasmic features such as secretory granules. The basal surface of an epithelium lies in contact with a thin layer of filamentous protein and proteoglycan termed the | 72 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Epithelia
29
CHAPTER 2
Sensory epithelia
Sensory epithelia are found in special sense organs of the olfactory,
gustatory and vestibulocochlear receptor systems. All of these contain
sensory cells surrounded by supportive non-receptor cells. Olfactory
receptors are modified neurones and their axons pass directly to the
brain, but the other types are specialized epithelial cells that synapse
with terminals of afferent (and sometimes efferent) nerve fibres.
Myoepithelial cells
Myoepithelial cells, which are also sometimes termed basket cells, are fusiform or stellate in shape ( Fig. 2.3), contain actin and myosin fila -
ments, and contract when stimulated by nervous or endocrine signals. They surround the secretory portions and ducts of some glands, e.g.
mammary, lacrimal, salivary and sweat glands, and lie between the
basal lamina and the glandular or ductal epithelium. Their contraction
assists the initial flow of secretion into larger conduits. Myoepithelial
cells are ultrastructurally similar to smooth muscle cells in the arrange -
ment of their actin and myosin, but differ from them because they originate, like the glandular cells, from embryonic ectoderm or endo -
derm. They can be identified immunohistochemically on the basis of the co-localization of myofilament proteins (which signify their con -
tractile function ( Fig. 2.4)) and keratin intermediate filaments (which
accords with their epithelial lineage).
Multilaminar (stratified) epithelia
Multilaminar epithelia are found at surfaces subjected to mechanical damage or other potentially harmful conditions. They can be divided
into those that continue to replace their surface cells from deeper layers,
designated stratified squamous epithelia, and others in which replace -
ment is extremely slow except after injury.
Stratified squamous epithelia
Stratified squamous epithelia are multilayered tissues in which the
formation, maturation and loss of cells is continuous, although the rates of these processes can change, e.g. after injury. New cells are formed in the most basal layers by the mitotic division of stem cells and transit (or transient) amplifying cells. The daughter cells move more superficially, changing gradually from a cuboidal shape to a more are polygonal when sectioned horizontally. Commonly, microvilli are
found on their free surfaces, which considerably increases the absorp -
tive area, e.g. in the epithelia of the small intestine (columnar cells with a striated border of very regular microvilli), the gallbladder (columnar
cells with a brush border of microvilli); proximal convoluted tubules
of the kidney (large cuboidal to low columnar cells with brush borders);
and the epididymis (columnar cells with extremely long microvilli,
erroneously termed stereocilia).
Ciliated columnar epithelium lines most of the respiratory tract,
except for the lower pharynx and vocal folds, and it is pseudostratified
(Fig. 2.2D) as far as the larger bronchioles; it also lines some of the
tympanic cavity and auditory tube; the uterine tube; and the efferent
ductules of the testis. Submucosal mucous glands and mucosal goblet
cells secrete mucus on to the luminal surface of much of the respira -
tory tract, and cilia sweep a layer of mucus, trapped dust particles and so on from the lung towards the pharynx in the mucociliary rejection
current, which clears the respiratory passages of inhaled particles. Cilia
in the uterine tube assist the passage of oocytes and fertilized ova to
the uterus.
Some columnar cells are specialized for secretion, and aggregates of
such cells may be described as glandular tissue. Their apical domains
typically contain mucus- or protein-filled (zymogen) vesicles, e.g.
mucin-secreting and chief cells of the gastric epithelium. Where mucous
cells lie among non-secretory cells, e.g. in the intestinal epithelium,
their apical cytoplasm and its secretory contents often expand to
produce a characteristic cell shape, and they are known as goblet cells
(see Fig. 2.2D). For further details of glandular tissue, see page 32, and
for the characteristics of mucus, see page 40.
Pseudostratified epithelium
Pseudostratified epithelium is a single-layered (simple) columnar epi -
thelium in which nuclei lie at different levels in a vertical section (Fig. 2.2D). All cells are in contact with the basal lamina throughout their
lifespan, but not all cells extend through the entire thickness of the
epithelium. Some constitute an immature basal cell layer of smaller cells, which are often mitotic and able to replace damaged mature cells. Migrating lymphocytes and mast cells within columnar epithelia may also give a similar, pseudostratified appearance because their nuclei are found at different depths. Much of the ciliated lining of the respiratory tract is of the pseudostratified type, and so is the sensory epithelium of the olfactory area.Fig. 2.1 Classification of epithelial tissues and cells. Squamous
Cuboidal
ColumnarSee also:
Mesothelium – lining body cavities
Endothelium – lining blood and lymphatic vessels
Without surface
specializationSecretory
With microvilli
(brush/striated border)PseudostratifiedCiliatedStratified squamous
Stratified cuboidal/columnar
Urothelial (transitional)Non-keratinizing
Relaxed StretchedKeratinizing
COMPLEX DERIVED STRUCTURES
• Multicellular – exocrine and endocrine glands• Sensory structures – e.g. taste buds
• Tooth germUNILAMINAR (SIMPLE) MULTILAMINAR
Specializations
• Nervous tissue – often classified separately , but retains many
characteristics of its epithelial origins
• Seminiferous epithelium | 73 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
INTE gRATIN g CEllS INTO TISS uES
30 SECTION 1
Fig. 2.2 A, Simple squamous epithelium lining the outer parietal layer (arrows) of a Bowman’s capsule in the renal corpuscle (RC), stained with the
trichrome, Martius Scarlet Blue (MSB). Oval epithelial nuclei project into the urinary space (U), within a highly attenuated cytoplasm. B, Simple cuboidal
epithelium lining a group of collecting ducts sectioned longitudinally in the renal medulla. The basement membranes are stained magenta with periodic–
acid Schiff (PAS) reagent. C, Simple columnar epithelium covering the tip (off field, right) of a villus in the ileum. Tall, columnar absorptive cells with oval,
vertically orientated nuclei bear a striated border of microvilli, just visible as a deeper-stained apical fringe. Numerous interspersed goblet cells are
present, with pale apical cytoplasm filled with mucinogen secretory granules and dark, flattened, basally situated nuclei. D, Ciliated columnar
pseudostratified epithelium in the respiratory tract, and interspersed goblet cells, with pale, mucinogen granule-filled apical cytoplasm. All human tissues. (All human tissues, courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
AUU
RC
B
C
D
Fig. 2.3 Stellate myoepithelial cells (M) wrapped around secretory acini in
the lactating mouse mammary gland, seen in the scanning electron microscope after enzymatic depletion of extracellular matrix. Blood
capillaries (C) and fibroblasts (F) are also indicated. (Courtesy of
Prof. Toshikazu Nagato, Fukuoka Dental College, Japan.)
CCF
MF
MM
CCF
MF
MM
Fig. 2.4 Myoepithelial cells (stained brown), in a human breast duct,
demonstrated immunohistochemically using antibody to smooth muscle
actin. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
| 74 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Epithelia
31
CHAPTER 2
general shape as are seen in the keratinized type, but they do not fill
completely with keratin or secrete glycolipid, and they retain their
nuclei until they desquamate at the surface. In sites where considerable
abrasion occurs, e.g. parts of the buccal cavity, the epithelium is thicker
and its most superficial cells may partly keratinize, so that it is referred
to as parakeratinized, in contrast to the orthokeratinized state of fully
keratinized epithelium. Diets deficient in vitamin A may induce kerati -
nization of such epithelia, and excessive doses may lead to its transfor -
mation into mucus-secreting epithelium.
Stratified cuboidal and columnar epithelia
Two or more layers of cuboidal or low columnar cells ( Fig. 2.5C) are
typical of the walls of the larger ducts of some exocrine glands, e.g. the pancreas, salivary glands and the ducts of sweat glands, and they pre -
sumably provide more strength than a single layer. Parts of the male urethra are also lined by stratified columnar epithelium. The layers are
not continually replaced by basal mitoses and there is no progression
of form from base to surface, but they can repair themselves if damaged.
Urothelium (urinary or
transitional epithelium)
Urothelium (Fig. 2.5D) is a specialized epithelium that lines much of the urinary tract and prevents its rather toxic contents from damaging
surrounding structures. It extends from the ends of the collecting ducts
of the kidneys, through the ureters and bladder, to the proximal portion
of the urethra. In males it lines the urethra as far as the ejaculatory ducts, then becomes intermittent and is finally replaced by stratified columnar epithelium in the membranous urethra. In females it extends as far as the urogenital membrane.
The epithelium appears to be 4–6 cells thick and lines organs that
undergo considerable distension and contraction. It can therefore stretch greatly without losing its integrity. In stretching, the cells become flattened form, and are eventually shed from the surface as a highly
flattened squame. Typically, the cells are held together by numerous
desmosomes to form strong, contiguous cellular sheets that provide
protection to the underlying tissues against mechanical, microbial and
chemical damage. Stratified squamous epithelia may be broadly subdi -
vided into keratinized and non-keratinized types.
Keratinized epithelium
Keratinized epithelium ( Fig. 2.5A) is found at surfaces that are subject
to drying or mechanical stresses, or are exposed to high levels of abra -
sion. These include the entire epidermis and the mucocutaneous junc -
tions of the lips, nostrils, distal anal canal, outer surface of the tympanic membrane and parts of the oral lining (gingivae, hard palate and fili -
form papillae on the anterior part of the dorsal surface of the tongue). Their cells, keratinocytes, are described in more detail on page 141. A
distinguishing feature of keratinized epithelia is that cells of the super-ficial layer, the stratum corneum, are anucleate, dead, flattened squames
that eventually flake off from the surface. In addition, the tough keratin
intermediate filaments become firmly embedded in a matrix protein.
This unusual combination of strongly coherent layers of living cells and
more superficial strata made of plates of inert, mechanically robust
protein complexes, interleaved with water-resistant lipid, makes this
type of epithelium an efficient barrier against different types of injury,
microbial invasion and water loss.
Non-keratinized epithelium
Non-keratinized epithelium is present at surfaces that are subject to
abrasion but protected from drying ( Fig. 2.5B). These include: the
buccal cavity (except for the areas noted above); oropharynx and laryn -
gopharynx; oesophagus; part of the anal canal; vagina; distal uterine cervix; distal urethra; cornea; inner surfaces of the eyelids; and the vestibule of the nasal cavities. Cells go through the same transitions in Fig. 2.5 A, Keratinized stratified squamous epithelium in thin skin. Pigmented melanocytes are seen in the basal layer and a few keratinocytes of the
prickle cell layer also contain melanin granules. The dead, keratinized layer (K) lacks nuclei. B, Non-keratinized stratified squamous epithelium of the
uterine ectocervix, stained with periodic–acid Schiff (PAS) reagent. The basement membrane (short arrows) and superficial squames, which retain their
nuclei, are PAS-positive; squames sloughing off the surface are indicated (long arrow). C, Stratified low columnar epithelium of an interlobular excretory
duct of the sublingual salivary gland. D, Urothelium (transitional epithelium) lining the relaxed urinary bladder. The most superficial cells have a thickened
plasma membrane as a result of the presence of intramembranous plaques, which give an eosinophilic appearance to the luminal surface (arrows). All
human tissues. (All human tissues, courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall
Hospitals Trust, UK.)
K
A
B
C
D | 75 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
INTE gRATIN g CEllS INTO TISS uES
32 SECTION 1
secrete small amounts of protein by a merocrine mechanism, and have
been reclassified as merocrine glands.
In apocrine glands, some of the apical cytoplasm is pinched off with
the contained secretions, which are stored in the cell as membrane-free
droplets (see Fig. 2.6). The best-understood example of this is the secre -
tion of milk fat by mammary gland cells, in which a small amount of cytoplasm is incorporated into the plasma membrane-bound lipid
globule as it is released from the cell. Larger amounts of cytoplasm are
included in secretions by specialized apocrine sweat glands in the axilla
(Stoeckelhuber et al 201 1) and anogenital regions of the body. In some
tissues there is a combination of different types of secretion, e.g.
mammary gland cells secrete milk fat by apocrine secretion and milk
protein, casein, by merocrine secretion.
In holocrine glands (see Fig. 2.6), e.g. sebaceous glands in the skin,
the cells first fill with secretory products (lipid droplets or sebum, in
this instance), after which the entire cell disintegrates to liberate the
accumulated mass of secretion into the adjacent duct or, more usually,
hair follicle.
Structural and functional classification
Exocrine glands are either unicellular or multicellular. The latter may be in the form of simple sheets of secretory cells, e.g. the lining of the
stomach, or may be structurally more complex and invaginated to a
variable degree. Such glands (see Fig. 2.6) may be simple units or their
connection to the surface may be branched. Simple unbranched tubular glands exist in the walls of many of the hollow viscera, e.g. the small
intestine and uterus, whereas some simple glands have expanded, flask-
like ends (acini or alveoli). Such glands may consist entirely of secretory
cells, or may have a blind-ending secretory portion that leads through
a non-secretory duct to the surface, in which case the ducts may modify
the secretions as they pass along them.
Glands with ducts may be branched (compound) and sometimes
form elaborate ductal trees. Such glands generally have acinar or alveo -
lar secretory lobules, as in the exocrine pancreas, but the secretory units may alternatively be tubular or mixed tubulo-acinar. More than one
type of secretory cell may occur within a particular secretory unit, or
individual units may be specialized to just one type of secretion (e.g.
serous acini of salivary glands).
Exocrine glands are also classified by their secretory products. Secre -
tory cells in mucus-secreting or mucous glands have frothy cytoplasm
and basal, flattened nuclei. They stain deeply with metachromatic stains
and periodic acid–Schiff (PAS) methods that detect carbohydrate resi -
dues. However, in general (i.e. non-specific) histological preparations, they are weakly stained because much of their content of water-rich
mucin has been extracted by the processing procedures. Secretory cells
in serous glands have centrally placed nuclei and eosinophilic secretory
storage granules in their cytoplasm. They secrete mainly glycoproteins
(including lysozyme) and digestive enzymes.
Some glands are almost entirely mucous (e.g. the sublingual salivary
gland), whereas others are mainly serous (e.g. the parotid salivary
gland). The submandibular gland is mixed, in that some lobules are
predominantly mucous and others serous. Mucous acini may share a
lumen with clusters of serous cells (seen in routine preparations as
serous demilunes). Although this simple approach to classification is
useful for general descriptive purposes, the diversity of molecules syn -
thesized and secreted by glands is such that complex mixtures often exist within the same cell.
ENDOCRINE GLANDS
Endocrine glands secrete directly into connective tissue interstitial fluid
and thence the circulation. Their cells are grouped around beds of capil-
laries or sinusoids, which typically are lined by fenestrated endothelia
to allow the rapid passage of macromolecules through their walls.
Endocrine cells may be arranged in clusters within vascular networks,
in cords between parallel vascular channels or as hollow structures (fol-
licles) surrounding their stored secretions. In addition to the cells of
specialized ductless endocrine glands (e.g. pituitary, pineal, thyroid and
parathyroid), hormone-producing cells also form components of other
organ systems. These include: the cells of the pancreatic islets; thymic
epithelial cells; renin-secreting cells of the kidney juxtaglomerular appa -
ratus; erythropoietin-secreting cells of the kidney; circumventricular organs; interstitial testicular (Leydig) cells; interstitial follicular and luteal ovarian cells; and placental cells (in pregnancy). Some cardiac myocytes, particularly in the walls of the atria, also have endocrine functions. These cells are all described in detail within the appropriate regional sections.flattened without altering their positions relative to each other, because
they are firmly connected by numerous desmosomes. However, the
urothelium appears to be reduced to only 2–3 cells thick. The epithe -
lium is called transitional because of the apparent transition from a stratified cuboidal epithelium to a stratified squamous epithelium,
which occurs as it is stretched to accommodate urine, particularly in
the bladder. The basal cells are basophilic and contain many ribosomes;
they are uninucleate (diploid), and cuboidal when relaxed. More api -
cally, they form large binucleate or, more often, polyploid uninucleate cells. The surface cells are the largest and may even be octoploid; in the
relaxed state they typically bulge into the lumen as dome-shaped cells
with a thickened, eosinophilic glycocalyx or cell coat. Their luminal
surfaces are covered by a specialized plasma membrane in which
plaques of intramembranous glycoprotein particles are embedded to
stiffen the membrane. When the epithelium is relaxed, the surface area
of the cells is reduced and the plaques are partially internalized by the
hinge-like action of the more flexible interplaque membrane regions.
The plaques re-emerge on to the surface when it is stretched.
Normally, cell turnover is very slow; cell division is infrequent and
is restricted to the basal layer. However, when damaged, the epithelium
regenerates quite rapidly.
Seminiferous epithelium
Seminiferous epithelium is a highly specialized, complex stratified epi-thelium. It consists of a heterogeneous population of cells that form
the lineage of the spermatozoa (spermatogonia, spermatocytes, sper-
matids), together with supporting cells (Sertoli cells). It is described in
detail on page 1275.
GLANDS
One of the features of many epithelia is their ability to alter the environ -
ment facing their free surfaces by the directed transport of ions, water
or macromolecules. This is particularly well demonstrated in glandular
tissue, in which the metabolism and structural organization of the cells
are specialized for the synthesis and secretion of macromolecules,
usually from the apical surface. Such cells may exist in isolation amongst
other non-secretory cells of an epithelium, e.g. goblet cells in the
absorptive lining of the small intestine, or may form highly coherent
sheets of epithelium with a common secretory function, e.g. the mucous
lining of the stomach and, in a highly invaginated structure, the complex
salivary glands.
Glands may be subdivided into exocrine glands and endocrine
glands. Exocrine glands secrete, usually via a duct, on to surfaces that
are continuous with the exterior of the body, including the alimentary
tract, respiratory system, urinary and genital ducts and their derivatives,
and the skin. Endocrine glands are ductless and secrete hormones
directly into interstitial fluid and thence the circulatory system, which
conveys them throughout the body to affect the activities of other cells.
In addition to strictly epithelial glands, some tissues derived from the
nervous system, including the suprarenal medulla and neurohypophy -
sis, are neurosecretory.
Paracrine glandular cells are similar to endocrine cells but their
secretions diffuse locally to cellular targets in the immediate vicinity; many are classed as neuroendocrine cells because they secrete mole-
cules used elsewhere in the nervous system as neurotransmitters or
neuromodulators. Modes of signalling by secretory cells are illustrated
in Figure 1.6.
EXOCRINE GLANDS
Types of secretory process
The mechanism of secretion varies considerably. If the secretions are
initially packaged into membrane-bound vesicles, these are conveyed
to the cell surface, where they are discharged. In merocrine secretion,
which is by far the most common secretory mechanism, vesicle mem -
branes fuse with the plasma membrane to release their contents to the exterior (Fig. 2.6). Specialized transmembrane molecules in the secre -
tory vesicle wall recognize marker proteins on the cytoplasmic side of
the plasma membrane and bind to them. This initiates interactions with other proteins that cause the fusion of the two membranes and the consequent release of the vesicle contents. The stimulus for secretion varies with the type of cell but often appears to involve a rise in intracel -
lular calcium. Glands such as the simple sweat glands of the skin, where ions and water are actively transported from plasma as an exudate, were once classified as eccrine glands. They are now known to synthesize and | 76 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
glands
33
CHAPTER 2
Isolated endocrine cells also exist scattered amongst other tissues as
part of the dispersed (diffuse) neuroendocrine system, e.g. throughout
the alimentary and respiratory tracts. Neuroendocrine cells are generally
situated within a mucosal epithelium and their bases often rest on the
basal lamina (see below). In response to an external stimulus, they
secrete their product basally into interstitial fluid. A typical neuroendo -
crine cell is shown in Figure 2.7. The secretory granules vary in shape,
size and ultrastructure according to cell type. Cells often take the name
of the secretion they produce, e.g. gastrin-secreting G cells of the small
intestine. Neuroendocrine cells share many of their secretory products
with chemical mediators in the nervous system.
CONTROL OF GLANDULAR SECRETION
The activities of cells in the various tissue and organ systems of the body
are tightly regulated by the coordinated activity of the endocrine and
autonomic nervous systems. Endocrine (and paracrine) signals reach target cells in interstitial fluid, often via blood plasma, and together with autonomic nervous signals they ensure that the body responds to normal physiological stimuli and adjusts to changes in the external environment. Hormone secretion is itself controlled in a number of ways, e.g. by neural control, regulatory feedback loops or according to various cyclical, rhythmical or pulsatile patterns of release. Endocrine Fig. 2.6 Classification of the different types of epithelial gland. Mechanisms of secretion
Structural classification of glands – Simple glands with unbranched ducts
Structural classification of glands – Ductal branching pattern of complex glandsA. Merocrine B. Apocrine C. Holocrine A. Unicellular B. Multicellular sheet
A. Simple tubular without duct B. Simple tubular with duct C. Simple branched tubular E. Simple acinar or alveolar D. Simple coiled tubular
B. Branched acinar/alveolar C. Branched tubulo-acinar A. Branched tubularArrangement of cells
glands have a rich vascular supply and their blood flow is controlled
by autonomic vasomotor nerves, which can thus modify glandular
activity.
Glandular activity may also be controlled directly by autonomic
secretomotor fibres, which may either form synapses on the bases of
gland cells (e.g. in the suprarenal medulla) or release neuromediators
in the vicinity of the glands and reach them by diffusion. Alternatively,
the autonomic nervous system may act indirectly on gland cells, e.g.
on neuroendocrine G cells via histamine, released neurogenically
from another neuroendocrine cell in the gastric lining. Such paracrine
activities of neuroendocrine cells are also important in the respiratory
system.
Circulating hormones from the adenohypophysis stimulate syn -
thesis and secretion by target cells in many endocrine glands. Such signals, mostly detected by receptors at the cell surface and mediated
by second messenger systems, may increase the synthetic activity of
gland cells, and may cause them to discharge their secretions by exocy -
tosis. Secretions from certain exocrine glandular cells are expressed
rapidly from those glands by the contraction of associated myoepithe -
lial cells (see Figs 2.3, 2.4) that enclose the secretory units and smaller
ducts. Myoepithelial cells may be under direct neural control, as in the salivary glands, or they may respond to circulating hormones, as in the mammary gland, where they respond to the concentration of circulat -
ing oxytocin. | 77 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
INTE gRATIN g CEllS INTO TISS uES
34 SECTION 1
plasma membrane proteins, e.g. keratinocyte hemidesmosomes are
anchored into the lamina densa in the basal lamina of the epidermis.
The basal lamina is a delicate felt-like network composed largely of two
glycoprotein polymers, laminin and type IV collagen, which self-
assemble into two-dimensional sheets interwoven with each other.
Early embryonic basal lamina is formed only of the laminin polymer.
Two other molecules cross-link and stabilize the network: entactin
(nidogen) and perlecan (a large heparan sulphate proteoglycan).
Although all basal laminae have a similar form, their thickness and
precise molecular composition vary between tissues and even within a
tissue, e.g. between the crypts and villi of the small intestine. The iso -
forms of laminin and collagen type IV differ in various tissues; thus Schwann cells and muscle cells express laminin-2 (merosin) rather than
the prototypical laminin-1. Laminin-5, although not itself a basal
lamina component, is found in the hemidesmosomes of the basal
epidermis and links the basal lamina with epidermal transmembrane
proteins, α
6β4 integrin and collagen type XVII (BPAG2, bullous pem -
phigoid antigen 2, one of the targets of the autoimmune blistering skin disease, bullous pemphigoid). The particular isoform of collagen type
IV in the basal lamina of different tissues is reflected in tissue-specific
disease patterns. Mutations in a collagen expressed by muscle and
kidney glomeruli cause Alport’s syndrome, a form of renal failure. Renal
failure also occurs in Goodpasture’s syndrome, in which renal basal
lamina collagen is targeted by autoantibodies.
In Descemet’s membrane in the cornea, collagen type VIII replaces
collagen type IV in the much thickened (increasing with age, up to
10 µm,) endothelial basal lamina. The basal lamina of the neuromus -
cular junction contains agrin, a heparan sulphate proteoglycan, which
plays a part in the clustering of muscle acetylcholine receptors in the
plasma membrane at these junctions.
RETICULAR LAMINA
The reticular lamina consists of a dense extracellular matrix that con -
tains collagen. In skin, it contains fibrils of type VII collagen (anchoring
fibrils), which bind the lamina densa to the adjacent connective tissue.
The high concentration of proteoglycans in the reticular lamina is
responsible for the positive reaction of the entire basement membrane
to stains for carbohydrates, which is seen in sections prepared for light
microscopy.
FUNCTIONS OF BASAL LAMINA
Basal laminae perform a number of important roles (Iozzo 2005). They
form selectively permeable barriers (anionic filters) between adjacent tissues, e.g. in the glomerular filter of the kidney; anchor epithelial and Feedback loops and endocrine axes
The pituitary gland, in particular the adenohypophysis, is often termed
the master gland because of its central role in endocrine physiological
processes. It provides the means by which the central nervous system
regulates and integrates, by non-neural mechanisms, the widespread
functions of the body, including the activities of other endocrine glands
and, often indirectly, exocrine glands such as the breast. Regulatory
hormones from the adenohypophysis stimulate synthesis and secretion
in target cells of many endocrine glands; these glands therefore respond
to, as well as generate, hormonal signals.
The hypothalamus and the adenohypophysis in the brain are central
to most regulatory feedback loops within the endocrine system. Loops
can be either positive or negative, e.g. the hypothalamus stimulates
release of follicle stimulating hormone (FSH) by the adenohypophysis,
which in turn stimulates ovarian follicular maturation and secretion of
oestradiol, which acts on breast and endometrial target tissues. Oestra -
diol, in this case, also acts back on the adenohypophysis and hypotha -
lamus to reinforce their function positively in a feedback loop. In
contrast, hypothalamic and adenohypophysial stimulation of testicular
production of testosterone, which acts on targets such as skeletal
muscle, is negatively regulated in a feedback loop generated by circulat -
ing testosterone. Such negative feedback regulation is a widely utilized physiological mechanism.
BASEMENT MEMBRANE AND BASAL LAMINA
There is a narrow layer of extracellular matrix, which stains strongly for carbohydrates, at the interface between connective and other tissues,
e.g. between epithelia and their supporting connective tissues. In early
histological texts this layer was termed the basement membrane.
As almost all of its components are synthesized by the epithelium or other tissues, rather than the adjacent connective tissue, it will be dis-
cussed here.
Electron microscopy revealed that the basement membrane is com -
posed of two distinct components. A thin, finely fibrillar layer, the basal
lamina, is associated closely with the basal cell surface ( Fig. 2.8). A
variable reticular lamina of larger fibrils and glycosaminoglycans of the extracellular matrix underlies this layer and is continuous with the con -
nective tissue proper, although it is much reduced or largely absent in some tissues, e.g. surrounding muscle fibres, Schwann cells and capil-
lary endothelia. In other tissues, the basal lamina separates two layers
of cells and there are no intervening typical connective tissue elements.
This occurs in the thick basal lamina of the renal glomerular filter and
the basal lamina of the thin portions of the lung interalveolar septa
across which gases exchange between blood and air.
The basal lamina is usually about 80 nm thick, varying between 40
and 120 nm, and consists of a sheet-like fibrillar layer, the lamina densa
(20–50 nm wide), separated from the plasma membrane of the cell it
supports by a narrow electron-lucent zone, the lamina lucida. The lamina lucida is absent from tissues prepared by rapid freezing and so may be an artefact. In many tissues this zone is crossed by integral
Fig. 2.8 The basal lamina as seen in an electron micrograph, underlying
the basal epithelial layer of human skin (see Fig. 7.3). The finely fibrillar
dense layer (long arrows) corresponds to the lamina densa, and fine
collagen fibrils (*) lie in the subjacent connective tissue. These contribute
to the appearance of the basement membrane in light microscope
preparations stained for carbohydrate-rich structures. The two cells seen
in the upper field are basal keratinocytes (K), joined by desmosomes
(short arrow), with dense keratin filaments in their cytoplasm. (Courtesy of
J McMillan MD, St John’s Institute of Dermatology, St Thomas’ Hospital,
London.)
K
KFig. 2.7 An electron
micrograph of a neuroendocrine cell
between two absorptive
cells in the colon
(rat tissue). Dense neurosecretory granules
are seen in the basal
cytoplasm, apposed
to the basal lamina (arrows). (Courtesy of
Michael Crowder MD.) | 78 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Connective and supporting tissues
35
CHAPTER 2
to demand. Embryologically, fibroblasts and adipocytes arise from mes-
enchymal stem cells, some of which may remain in the tissues to
provide a source of replacement cells postnatally. As noted above, the
cells of haemopoietic origin migrate into the tissue from bone marrow
and lymphoid tissue.
Resident cells
Fibroblasts
Fibroblasts are usually the most numerous resident cells. They are flat -
tened and irregular in outline, with extended processes, and in profile
they appear fusiform or spindle-shaped (Fig. 2.10; see also Fig. 2.12).
Fibroblasts synthesize most of the extracellular matrix of connective tissue (see Fig. 2.10); accordingly, they have all the features typical of
cells active in the synthesis and secretion of proteins. Their nuclei are relatively large and euchromatic, and possess prominent nucleoli. In
young, highly active cells, the cytoplasm is abundant and basophilic
(reflecting the high concentration of rough endoplasmic reticulum),
mitochondria are abundant and several sets of Golgi apparatus are
present. In old and relatively inactive fibroblasts (often termed fibro -
cytes), the cytoplasmic volume is reduced, the endoplasmic reticulum is sparse and the nucleus is flattened and heterochromatic.
Fibroblasts are usually adherent to the fibres of the matrix (collagen
and elastin), which they lay down. In some highly cellular structures,
e.g. liver, kidney and spleen, and in most lymphoid tissue, fibroblasts
and delicate collagenous fibres (type III collagen; reticular fibres) form
fibrocellular networks, which are often called reticular tissue. The
fibroblasts may then be termed reticular cells or reticulocytes.
Fibroblasts are particularly active during wound repair following
traumatic injury or inflammation, when tissue mass is lost through cell
death. They proliferate and lay down a fibrous matrix that becomes
invaded by numerous blood vessels (granulation tissue). Contraction
of wounds is, at least in part, caused by the shortening of myofibrob -
lasts, specialized contractile fibroblast-like cells (Hinz et al 2012) with
properties similar to smooth muscle cells. It was thought that myofi -
broblasts differentiated from fibroblasts (reviewed in McAnulty (2007))
or their progenitor mesenchymal stem cells (see below) in granulation tissue. However, recent evidence suggests that in wound healing and in
many fibrotic disease processes, including hepatic cirrhosis, the myofi -
broblast precursor is the vascular pericyte or a closely related cell (reviewed in Duffield (2012)). In cases where the specialized cells of
the damaged region cannot divide and regenerate functional tissue, e.g. cardiac muscle cells after infarction, connective tissue fibroblasts and
their extracellular matrix fill the void to form a scar. An exception is the
central nervous system, where glial scars are formed after injury. Fibrob -
last activity is influenced by various factors such as steroid hormone
concentration, dietary content and prevalent mechanical stresses. Col -
lagen formation is impaired in vitamin C deficiency.
Adipocytes (lipocytes, fat cells)
Adipocytes occur singly or in groups in many, but not all, connective tissues. They are numerous in adipose tissue ( Fig. 2.1 1). Individually, connective tissues, and so stabilize and orientate the tissue layers; may
exert instructive effects on adjacent tissues, and so determine their polar -
ity, rate of cell division, cell survival, etc.; and regulate angiogenesis. In addition, they may act as pathways for the migration and pathfinding
activities of growing cell processes, both in development and in tissue
repair, e.g. in guiding the outgrowth of axons and the re-establishment
of neuromuscular junctions during regeneration after injury in the
peripheral nervous system. Changes in basal lamina thickness are often
associated with pathological conditions, e.g. the thickening of the
glomerular basal lamina in glomerulonephritis and diabetes.
CONNECTIVE AND SUPPORTING TISSUES
The connective tissues are defined as those composed predominantly of intercellular material, the extracellular matrix, which is secreted
mainly by the connective tissue cells. The cells are therefore usually widely separated by their matrix, which is composed of fibrous proteins
and a relatively amorphous ground substance ( Fig. 2.9). Many of the
special properties of connective tissues are determined by the composi -
tion of the matrix, and their classification is also largely based on its
characteristics. In some types of connective tissue, the cellular compo -
nent eventually dominates the tissue, even though the tissue originally
has a high matrix : cell ratio, e.g. adipose tissue. Connective tissues are
derived from embryonic mesenchyme or, in the head region, largely
from neural crest.
Connective tissues have several essential roles in the body. These may
be subdivided into structural roles, which largely reflect the special mechanical properties of the extracellular matrix components, and
defensive roles, in which the cellular component has the dominant role.
Connective tissues often also play important trophic and morphoge -
netic parts in organizing and influencing the growth and differentiation of surrounding tissues, e.g. in the development of glands from an epi-
thelial surface.
Structural connective tissues are divided into ordinary (or general)
types, which are widely distributed, and special skeletal types, i.e. car -
tilage and bone, which are described in Chapter 5. A third type, haemo -
lymphoid tissues, consists of peripheral blood cells, lymphoid tissues
and their precursors; these tissues are described in Chapter 4. They are
often grouped with other types of connective tissue because of their similar mesenchymal origins and because the various defensive cells of
the blood also form part of a typical connective tissue cell population.
They reach connective tissues via the blood circulation and migrate into
them through the endothelial walls of vessels.
CELLS OF GENERAL CONNECTIVE TISSUES
Cells of general connective tissues can be separated into the resident
cell population (fibroblasts, adipocytes, mesenchymal stem cells, etc.) and a population of migrant cells with various defensive functions (macrophages, lymphocytes, mast cells, neutrophils and eosinophils), which may change in number and moderate their activities according Fig. 2.9 General loose connective tissue (human), with bundles of
collagen fibres (C) within an amorphous ground substance, penetrated by
a neurovascular bundle of blood vessels (BV), lymphatics and nerves. A
small autonomic ganglion is arrowed. (Courtesy of Mr Peter Helliwell and
the late Dr Joseph Mathew, Department of Histopathology, Royal
Cornwall Hospitals Trust, UK.)
C BV
BV
Fig. 2.10 An electron
micrograph of a fibroblast in human
connective tissue,
surrounded by bundles
of finely banded
collagen fibrils (shown
at high magnification in
the insert), which they
secrete. (Courtesy
of Dr Bart Wagner, Histopathology
Department, Sheffield
Teaching Hospitals,
UK.) | 79 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
INTE gRATIN g CEllS INTO TISS uES
36 SECTION 1
nerve endings in adipose tissue is particularly important in this respect.
No new adipose tissue is thought to form after the immediate postnatal
period, and accumulation of body fat, as in obesity, is due to excessive
accumulation of lipid in existing adipocytes, which become very large.
Conversely, weight loss results from the mobilization and metabolism
of lipid from adipocyte stores, with the consequent shrinkage of the
cells.
Mesenchymal stem cells
Mesenchymal stem cells are normally inconspicuous cells in connective
tissues. They are derived from embryonic mesenchyme and are able to
differentiate into the mature cells of connective tissue during normal
growth and development, in the turnover of cells throughout life and,
most conspicuously, in the repair of damaged tissues in wound healing.
There is emerging evidence that, even in mature tissues, mesenchymal
stem cells remain pluripotent and able to give rise to all the resident
cells of connective tissues in response to local signals and cues. The
potential therapeutic use of mesenchymal stem cell-based therapy for
a wide range of autoimmune disorders and degenerative diseases is
reflected in a burgeoning literature in the field of translational medi -
cine. (See, for example, Ankrum and Karp (2010), Jackson et al (2012)
and Ren et al (2012)).
Migrant cells
Macrophages
Macrophages are numerous in connective tissues, where they are either
attached to matrix fibres or are motile and migratory ( Fig. 2.12). They
are relatively large cells, 15–20 µm in diameter, with indented and rela-
tively heterochromatic nuclei and a prominent nucleolus. Their cyto -
plasm is slightly basophilic, contains many lysosomes and typically has a foamy appearance under the light microscope. Macrophages are
important phagocytes and form part of the mononuclear phagocyte
system. They can engulf and digest particulate organic materials, such
as bacteria, and are able to clear dead or damaged cells from a tissue
too. They are also the source of a number of secreted cytokines that
have profound effects on many other cell types. Macrophages are able
to proliferate in connective tissues to a limited extent, but are derived and replaced primarily from haemopoietic stem cells in the bone marrow, which circulate in the blood as monocytes before migrating through vessel walls into connective tissues, where they differentiate.
Many properties of macrophages in general connective tissue are
similar to those of related cells in other sites. These include: circulating monocytes, from which they are derived; alveolar macrophages in the the cells are oval or spherical in shape, but when packed together they
are polygonal. They vary in diameter, averaging 50 µm. Each cell con -
sists of a peripheral rim of cytoplasm, in which the nucleus is embed-
ded, surrounding a single large central globule of fat, which consists of
glycerol esters of oleic, palmitic and stearic acids. There is a small accu -
mulation of cytoplasm around the oval nucleus, which is typically compressed against the cell membrane by the lipid droplet, together
with the Golgi complex. Many cytoskeletal filaments, some endoplas -
mic reticulum and a few mitochondria lie around the lipid droplet, which is in direct contact with the surrounding cytoplasm and not
enclosed within a membrane. In sections of tissue not specially treated
to preserve lipids, the lipid droplet is usually dissolved out by the sol -
vents used in routine preparations, so that only the nucleus and the peripheral rim of cytoplasm surrounding a central empty space remain.
Another form of adipose tissue, brown fat, occurs in the interscapu -
lar region of neonates, a location it shares with the classic brown fat of
rodents. Brown fat is characterized by the presence of large cells, each
of which contains several separate droplets of fat (multilocular adipose
tissue) rather than a single globule (typical of unilocular adipose tissue;
see above), and by mitochondria in which the cristae are unusually
large and numerous. White fat cells are specialized to store chemical
energy, whereas the physiological role of brown adipose tissue (BAT)
cells is to metabolize fatty acids and generate heat; BAT cells uncouple
cellular respiration via the mitochondrial uncoupling protein UCP1. It
had been thought that brown fat disappears during postnatal growth,
but significant deposits of UCP1-positive brown fat have been detected
by positron emission tomography (PET) scanning methods in adults,
mainly in the supraclavicular region, in the neck and along the spine.
Recent evidence suggests that these human UCP1-positive cells may not
be classic brown fat cells but a distinct type of thermogenic fat cell called
a beige fat cell, thought to be derived from precursor cells in white fat
(Wu et al 2012). Such cells may represent an evolutionarily conserved
cellular mechanism to provide flexibility in adaptive thermogenesis.
It has long been recognized that adipose tissue is central to the
control of energy balance and lipid homeostasis. There is a growing
view that it may play a similarly important role as an endocrine organ, secreting a class of peptides called adipokines (Trayhurn and Wood 2004), which may enter the blood via capillaries or lymph. Different types of adipose tissue display functional and regional heterogeneity and differ in their involvement with disease processes (reviewed in
Hassan et al (2012)). The mobilization of fat is under nervous or hor -
monal control; noradrenaline (norepinephrine) released at sympathetic Fig. 2.11 Adipose tissue (human, from a lymph node specimen).
Adipocytes (A) are distended polygonal cells filled with lipid, which has
been extracted by the tissue processing. This leaves only the plasma
membranes with scant cytoplasm and nuclei (arrows), occasionally visible
compressed against the cell periphery. Small blood vessels (BV) penetrate
the adipose tissue; larger vessels are seen on the right. (Courtesy of Mr
Peter Helliwell and the late Dr Joseph Mathew, Department of
Histopathology, Royal Cornwall Hospitals Trust, UK.)
AA
BV
BVBV
Fig. 2.12 Macrophages (M) in chronically inflamed human connective
tissue, showing prominent pigmented, haemosiderin-containing
cytoplasmic granules derived from ingested erythrocytes. Many are
multinucleate. Also seen are plasma cells (P), small lymphocytes (L) and
other haemopoietic cells. (Courtesy of Mr Peter Helliwell and the late Dr
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
LLM
MPP
P | 80 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Connective and supporting tissues
37
CHAPTER 2
CELLS OF SPECIALIZED CONNECTIVE TISSUES
Skeletal tissues – namely, cartilage and bone – are generally classified
with the connective tissues, but their structure and functions are highly
specialized and they are described in Chapter 5. As with the general
connective tissues, these specialized types are characterized by their extracellular matrix, which forms the major component of the tissues
and is responsible for their properties. The resident cells are different
from those in general connective tissues. Cartilage is populated by
chondroblasts, which synthesize the matrix, and by mature chondro-
cytes. Bone matrix is elaborated by osteoblasts. Their mature progeny,
osteocytes, are embedded within the matrix, which they help to min -
eralize, turn over and maintain. A third cell type, the osteoclast, has a different lineage origin and is derived from haemopoietic tissue; osteo -
clasts are responsible for bone degradation and remodelling in collabo -
ration with osteoblasts.
EXTRACELLULAR MATRIX
The term extracellular matrix is applied collectively to the extracellular components of connective and supporting tissues. Essentially, it con-
sists of a system of insoluble protein fibres, adhesive glycoproteins and
soluble complexes composed of carbohydrate polymers linked to
protein molecules (proteoglycans and glycosaminoglycans), which
bind water. The extracellular matrix distributes the mechanical stresses
on tissues and also provides the structural environment of the cells
embedded in it, forming a framework to which they adhere and on
which they can move (reviewed in Even-Ram and Yamada (2005) and
Wolf and Friedl (201 1)). With the exception of bone matrix, it provides a highly hydrated medium, through which metabolites, gases and nutri -
ents can diffuse freely between cells and the blood vessels traversing it or, in the case of cartilage, passing nearby.
There are many complex interactions between connective tissue cells
and the extracellular matrix. The cells continually synthesize, secrete,
modify and degrade extracellular matrix components, and respond to
contact with the matrix in the regulation of cell metabolism, prolifera -
tion and motility. Degradation of the matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair
and remodelling (Mott and Werb 2004). Various types of proteinase are
involved, principally metalloproteinases such as matrix metalloprotei -
nases (MMPs), and those with a disintegrin and metalloproteinase domain (ADAMs) that include ADAMs with a thrombospondin domain
(ADAMTS). Tissue remodelling depends on the controlled degradation
of the extracellular matrix by secreted MMPs, regulated by their specific
inhibitors, as occurs, for instance, during involution of the postpartum
uterus or during menstrual lysis and shedding of the endometrium
(Gaide Chevronnay et al 2012). In the process of matrix degradation,
bioactive peptides are liberated that act as growth factors, cytokines and
other signalling molecules to change the behaviour of cells in the vicin -
ity. While precisely regulated under physiological conditions, patho -
logically dysregulated extracellular matrix degradation is a cause of
many diseases, such as atherosclerosis, emphysema, osteoarthritis and
diabetic vascular complications.
The insoluble fibres are mainly of two types of structural pro-
tein: members of the collagen family, and elastin (Fig. 2.13). The lungs, which take up inhaled particles not cleared by the mucociliary
rejection current; phagocytic cells in the lymph nodes, spleen and bone
marrow; Kupffer cells of the liver sinusoids; and microglial cells of the
central nervous system.
Lymphocytes
Lymphocytes are normally present in small numbers; they are numer -
ous in general connective tissue only in pathological states, when they migrate in from adjacent lymphoid tissue or from the circulation. The
majority are small cells (6–8 µm) with highly heterochromatic nuclei
but they enlarge when stimulated. Two major functional classes exist, termed B and T lymphocytes. B lymphocytes originate in the bone
marrow, then migrate to various lymphoid tissues, where they prolifer -
ate. When antigenically stimulated, they undergo further mitotic divi -
sions, then enlarge as they mature, commonly in general connective
tissues, to form plasma cells that synthesize and secrete antibodies
(immunoglobulins). Mature plasma cells are rounded or ovoid, up to
15 µm across, and have an extensive rough endoplasmic reticulum.
Their nuclei are spherical, often eccentrically situated, and have a char -
acteristic ‘clock-face’ configuration of heterochromatin (see Fig. 4.12)
that is regularly distributed in peripheral clumps. The prominent Golgi
complex is visible with a light microscope as a pale region to one side
of the nucleus and the remaining cytoplasm is deeply basophilic
because of the abundant rough endoplasmic reticulum. Mature plasma
cells do not divide.
T lymphocytes originate from precursors in bone marrow haemo -
poietic tissue but later migrate to the thymus, where they develop T-cell
identity, before passing into the peripheral lymphoid system, where
they continue to multiply. When antigenically stimulated, T cells
enlarge and their cytoplasm becomes filled with free polysome clusters.
The functions of T lymphocytes are numerous: different subsets recog -
nize and destroy virus-infected cells, tissue and organ grafts, or interact with B lymphocytes and several other defensive cell types.
Mast cells
Mast cells are important defensive cells. They occur particularly in loose connective tissues and in the fibrous capsules of certain organs such as
the liver, and are numerous around blood vessels. Mast cells are round
or oval, approximately 20 µm in diameter, with many filopodia extend -
ing from the cell surface. The nucleus is centrally placed and relatively small. The cytoplasm contains large numbers of prominent vesicles and
a well-developed Golgi apparatus, but scant endoplasmic reticulum.
The vesicles have a high content of glycosaminoglycans and show a
strongly positive reaction with the PAS stain for carbohydrates. They are
membrane-bound, vary in size and shape (mean diameter 0.5 µm) and
also have a rather heterogeneous content of dense, lipid-containing
material, which may be finely granular, lamellar or in the form of
membranous whorls.
The major granule components, many of them associated with
inflammation (Frenzel and Hermine 2013), are the proteoglycan
heparin, histamine, tryptase, superoxide dismutase, aryl sulphatase,
β-hexosaminidase and various other enzymes, including chymase in
connective tissue but not mucosal mast cells, together with chemotactic
factors for neutrophil and eosinophil granulocytes. There are functional
differences between mast cells found in different tissues.
Mast cells may be stimulated to release some or all of their contents,
either by direct mechanical or chemical trauma, or after contact with
particular antigens to which the body has previously been exposed. The
consequences of granule release include alteration of capillary perme -
ability, smooth muscle contraction, and activation and attraction to the locality of various other defensive cells. Responses to mast cell degranu -
lation may be localized, e.g. urticaria, or there may occasionally be a generalized response to the release of large amounts of histamine into
the circulation (anaphylactic shock). Mast cells closely resemble
basophil granulocytes of the general circulation but are thought to
develop as distinct descendants of an earlier myeloid lineage precursor.
It is believed that they are generated in the bone marrow and circulate
to the tissues as immature basophil-like cells, migrating through the
capillary and venule walls to their final destination. For further reading,
see Bischoff (2007) and Collington et al (201 1).
Granulocytes (polymorphonuclear
leukocytes)
Neutrophil and eosinophil granulocytes are immigrant cells from the
circulation. Relatively infrequent in normal connective tissues, their numbers may increase dramatically in infected tissues, where they are important components of cellular defence. Neutrophils are highly phagocytic, especially towards bacteria. The functions of eosinophils are less well understood. These cells are described further in Chapter 4.
Fig. 2.13 Elastic fibres, seen as fine, dark, relatively straight fibres in a
whole-mount preparation of mesentery, stained for elastin. The wavy pink
bands are collagen bundles and oval grey nuclei are mainly of fibroblasts.
| 81 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
INTE gRATIN g CEllS INTO TISS uES
38 SECTION 1
ency. Tendons, aponeuroses and ligaments are also highly ordered
tissues (Ch. 5).
Types II, III, V and XI collagens
Types II, III, V and XI collagens can also aggregate to form linear fibrils.
Type II collagen occurs in extremely thin (10 nm), short fibrils in the
vitreous humour and in very thick fibrils in ageing human cartilage. The amino-acid sequence and banding pattern are very similar to those of
type I collagen, as are the post-translational modifications of the triple
helical protein molecule. The fine fibrils in the vitreous may fuse into
thicker aggregates in older tissue.
Type III collagen is very widely distributed, particularly in young and
repairing tissues. It usually co-localizes with type I collagen, and cova-
lent links between type I and type III collagen have been demonstrated.
In skin, many fibrils are probably composites of type I and type III
collagens.
Reticular fibres
Fine branching and anastomosing reticular fibres form the supporting
mesh framework of many glands, including the liver ( Fig. 2.14), the
kidney and lymphoreticular tissue (lymph nodes, spleen, etc.). Classi -
cally, these fibres stained intensely with silver salts, although they are
poorly stained using conventional histological techniques. They associ -
ate with basal laminae and are often found in the neighbourhood of collagen fibre bundles. Reticular fibres are formed principally of type
III collagen.
Elastin
Elastin is a 70 kDa protein, rich in the hydrophobic amino acids valine
and alanine. Elastic fibrils, which also contain fibrillin, are highly cross-linked via two elastin-specific amino acids, desmosine and iso-
desmosine, which are formed extracellularly from lysine residues. They
are less widely distributed than collagen, yellowish in colour, typically
cross-linked and usually thinner (10–20 nm) than collagen fibrils. They
can be thick, e.g. in the ligamenta flava and ligamentum nuchae. Unlike collagen type I, they show no banding pattern in the electron micro -
scope. They stain poorly with routine histological stains but are stained with orcein-containing preparations (see Fig. 2.13). They sometimes
appear as sheets, as in the fenestrated elastic lamellae of the aortic wall. Elastin-rich structures stretch easily with almost perfect recoil, although
they tend to calcify with age and lose elasticity. Elastin is highly resistant
to attack by acid and alkali, even at high temperatures.
Interfibrillar matrix
Glycosaminoglycans
The structural soluble polymers characteristic of the extracellular matrix
are the acidic glycosaminoglycans, which are unbranched chains of repeating disaccharide units, each unit carrying one or more negatively charged groups (carboxylate or sulphate esters, or both). The anionic charge is balanced by cations (Na
+, K+, etc.) in the interstitial fluid. Their
polyanionic character endows the glycosaminoglycans with high osmotic activity, which helps to keep the fibrils apart, confers stiffness interfibrillar matrix (ground substance) includes a number of adhesive
glycoproteins that perform a variety of functions in connective tissues,
including cell–matrix adhesion and matrix–cell signalling. These glyco -
proteins include fibronectin, laminin, tenascin and vitronectin, in
addition to a number of other less well characterized proteins. The
glycosaminoglycans of the interfibrillar matrix are, with one notable
exception, post-translationally modified proteoglycan molecules in
which long polysaccharide side chains are added to short core proteins
during transit through the secretory pathway between the rough endo -
plasmic reticulum and the trans-Golgi network. The exception, the poly -
meric disaccharide, hyaluronan, has no protein core and is synthesized
entirely by cell surface enzymes. For further reading on extracellular
matrix molecules, see Pollard et al (2008). Functional attributes of con -
nective tissues vary and depend on the abundance of its different com -
ponents. Collagen fibres resist tension, whereas elastin provides a measure of resilience to deformation by stretching. The highly hydrated,
soluble polymers of the interfibrillar material (proteoglycans and gly -
cosaminoglycans, mainly hyaluronan) generally form a stiff gel resisting compressive forces. Thus tissues that are specialized to resist tensile
forces (e.g. tendons) are rich in collagen fibrils; tissues that accommo -
date changes in shape and volume (e.g. mesenteries) are rich in elastic fibres; and those that absorb compressive forces (e.g. cartilages) are rich
in glycosaminoglycans and proteoglycans. In bone, mineral crystals take
the place of most of the soluble polymers and endow the tissue with
incompressible rigidity.
Fibrillar matrix
Collagens
Collagens make up a very large proportion (approximately 30%) of all
the proteins of the body. They consist of a wide range of related mol -
ecules that have various roles in the organization and properties of connective (and some other) tissues. The first collagen to be character -
ized was type I, the most abundant of all the collagens and a constituent of the dermis, fasciae, bone, tendon, ligaments, blood vessels and the
sclera of the eyeball. The characteristic collagen of cartilage and the
vitreous body of the eye, with a slightly different chemical composition,
is type II, whereas type III is present in several tissues, including the
dermis and blood vessels, and type IV is in basal lamina. The other
types are widely distributed in various tissues. Five of the collagens,
types I, II, III, V and XI, form fibrils; types IV, VIII and X form sheets or
meshworks; types VI, VII, IX, XII, XIV and XVIII have an anchoring or
linking role; and types XIII and XVII are transmembrane proteins.
Biochemically, all collagens have a number of features in common.
Unlike most other proteins, they contain high levels of hydroxyproline
and all are composed of three polypeptides that form triple helices and
are substantially modified post-translationally. After secretion, indi-
vidual molecules are further cross-linked to form stable polymers. Func -
tionally, collagens are structural proteins with considerable mechanical strength. Just a few of their distinguishing structural features are
described below. For further reading on the molecular structure and
functions of the collagens, see Pollard et al (2008).
Type I collagen
Type I collagen is very widely distributed. It forms inextensible fibrils in which collagen molecules (triple helices) are aligned side by side in
a staggered fashion, with three-quarters of the length of each molecule
in contact with neighbouring molecules. The fibril has well-marked
bands of charged and uncharged amino acids arranged across it; these
stain with heavy metals in a banding pattern that repeats every 65 nm
in longitudinal sections viewed in the electron microscope (see Fig. 2.10
insert).
Fibril diameters vary between tissues and with age. Developing
tissues often have thinner fibrils than mature tissues. Corneal stroma fibrils are of uniform and thin diameter, whereas tendon fibrils may be
up to 20 times thicker and quite variable. Tissues in which the fibrils
are subject to high tensile loading tend to have thicker fibrils. Thick
fibrils are composites of uniform thin fibrils with a diameter of 8–12 nm.
The fibrils themselves are relatively flexible, but when mineralized (as
in bone) or surrounded by high concentrations of proteo glycan (as in
cartilage), the resulting fibre-reinforced composite materials are rigid.
Fresh type I collagen fibres are tightly packed assemblies of parallel
fibrils and are white and glistening. They form variably wavy (crimped)
bundles of various sizes that are generally visible at the light microscope level. The component fibres may leave one bundle and interweave with others. In some situations, collagen fibrils are laid down in precise geo -
metrical patterns, in which successive layers alternate in direction, e.g. corneal stroma, where the high degree of order is essential for transpar -Fig. 2.14 Reticular fibres (type III collagen; reticulin demonstrated by
silver-staining) in human liver, forming a delicate meshwork within the
space of Disse between hepatocytes (H), plasma membranes and the
sinusoidal endothelia (S). (Courtesy of Mr Peter Helliwell and the late Dr
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
Trust, UK.)
HH
SS | 82 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Connective and supporting tissues
39
CHAPTER 2
Tenascin
Tenascin is large glycoprotein composed of six subunits that are joined
at one end to form a structure that resembles the spokes of a wheel.
There is a family of tenascin molecules, generated by alternative splicing
of the tenascin gene transcript. Tenascin is abundant in embryonic
tissues but its distribution is restricted in the adult. It appears to be
important in guiding cell migration and axonal growth in early develop -
ment: it may either promote or inhibit these activities, depending on the cell type and tenascin isoform.
CLASSIFICATION OF CONNECTIVE TISSUES
Connective and supporting tissues differ considerably in appearance, consistency and composition in different regions. These differences
reflect local functional requirements and are related to the predomi -
nance of the cell types; the concentration, arrangement and types of fibre; and the characteristics of the interfibrillar matrix. On these
bases, general connective tissues can be classified into irregular and regular types, according to the degree of orientation of their fibrous
components.
Irregular connective tissues
Irregular connective tissues can be further subdivided into loose, dense and adipose connective tissue.
Loose (areolar) connective tissue
Loose connective tissue is the most generalized form and is extensively distributed. Its chief function is to bind structures together, while still
allowing a considerable amount of movement to take place. It consti -
tutes the submucosa in the digestive tract and other viscera lined by mucosae, and the subcutaneous tissue in regions where this is devoid
of fat (e.g. eyelids, penis, scrotum and labia), and it connects muscles,
vessels and nerves with surrounding structures. It is present in the inte-
rior of organs, where it binds together the lobes and lobules of glands,
forms the supporting layer (lamina propria) of mucosal epithelia and
vascular endothelia, and lies within and between fascicles of muscle
and nerve fibres.
Loose connective tissue consists of a meshwork of thin collagen and
elastin fibres interlacing in all directions (see Fig. 2.13) to give a measure
of both elasticity and tensile strength. The large meshes contain the soft, semi-fluid interfibrillar matrix or ground substance, and different con -
nective tissue cells, which are scattered along the fibres or in the meshes. It also contains adipocytes, usually in small groups, and particularly
around blood vessels.
A variant of loose connective tissue occurs in the choroid and the
sclera of the eye, where large numbers of pigment cells (melanocytes)
are also present.
Dense irregular connective tissue
Dense irregular connective tissue is found in regions that are under
considerable mechanical stress and where protection is given to
ensheathed organs. The matrix is relatively acellular and contains a high
proportion of collagen fibres organized into thick bundles interweaving
in three dimensions and imparting considerable strength. There are few
active fibroblasts, which are usually flattened with heterochromatic
nuclei. Dense irregular connective tissue occurs in: the reticular layer of
the dermis; the superficial connective tissue sheaths of muscle and
nerves, and the adventitia of large blood vessels; and the capsules of
various glands and organs (e.g. testis, sclera of the eye, periostea and
perichondria).
Adipose tissue
A few adipocytes occur in loose connective tissue in most parts of the
body. However, they constitute the principal component of adipose
tissue (see Fig. 2.1 1), where they are embedded in a vascular loose con -
nective tissue, usually divided into lobules by stronger fibrous septa carrying the larger blood vessels. Adipose tissue only occurs in certain
regions. In particular it is found: in subcutaneous tissue; in the mesenter -
ies and omenta; in the female breast; in bone marrow; as retro-orbital
fat behind the eyeball; around the kidneys; deep to the plantar skin of the foot; and as localized pads in the synovial membrane of many joints. Its distribution in subcutaneous tissue shows characteristic age and sex differences. Fat deposits serve as energy stores, sources of meta -
bolic lipids, thermal insulation (subcutaneous fat) and mechanical shock-absorbers (e.g. soles of the feet, palms of the hands, gluteal region and synovial membranes).on the porous gel that they collectively create, and gives the tissue a
varying degree of basophilia. Glycosaminoglycans are named according
to the tissues in which they were first found, e.g. hyaluronan (vitreous
body), chondroitins (cartilage), dermatan (skin), keratan (cornea),
heparan (liver). This terminology is no longer relevant, as most gly -
cosaminoglycans are very widely distributed, whereas, conversely, some corneas contain little or no keratan sulphate. Of the glycosaminogly -
cans, all except hyaluronan have short protein cores and are highly variable in their carbohydrate side-chain structure.
Hyaluronan
Hyaluronan was formerly called hyaluronic acid (or hyaluronate, as
only the salt exists at physiological pH). It is a very large, highly hydrated
molecule (25,000 kDa). Hyaluronan is found in all extracellular matri -
ces and in most tissues, and is a prominent component of embryonic
and developing tissues.
Hyaluronan is important in the aggregation of proteoglycans and
link proteins that possess specific hyaluronan binding sites (e.g.
laminin). Indeed, the very large aggregates that are formed may be the
essential compression-resisting units in cartilage. Hyaluronan also
forms very viscous solutions, which are probably the major lubricants
in synovial joints. Because of its ability to bind water, it is often present
in semi-rigid structures (e.g. vitreous humour in the eye), where it
cooperates with sparse but regular meshworks of thin collagen fibrils.
Proteoglycans
Proteoglycans have been classified according to the size of their protein
core; their nomenclature is under review. The same core protein can
bear different glycosaminoglycan side chains in different tissues. The
functions of many proteoglycans are poorly understood. Some of the
better-known proteoglycans are: aggrecan in cartilage, perlecan in basal
laminae, decorin associated with fibroblasts in collagen fibril assembly,
and syndecan in embryonic tissues.
Adhesive glycoproteins
These proteins include molecules that mediate adhesion between cells
and the extracellular matrix, often in association with collagens, proteo -
glycans or other matrix components. All of them are glycosylated and
they are, therefore, glycoproteins. General connective tissue contains the
well-known families of fibronectins (and osteonectin in bone), lam -
inins and tenascins; there is a rapidly growing list of other glycoproteins
associated with extracellular adhesion (Pollard et al 2008). They possess
binding sites for other extracellular matrix molecules and for cell adhe -
sion molecules, especially the integrins; in this way they enable cells selectively to adhere to and migrate through, appropriate matrix struc -
tures (reviewed in Jacquemet et al (2013)). They also function as signal -
ling molecules, which are detected by cell surface receptors and initiate changes within the cytoplasm (e.g. to promote the formation of
hemidesmosomes or other areas of strong adhesion; reorganize the
cytoskeleton; and promote or inhibit locomotion and cell division).
Fibronectin
Fibronectin is a large glycoprotein consisting of a dimer joined by
disulphide links. Each subunit is composed of a string of large repetitive
domains linked by flexible regions. Fibronectin subunits have binding
sites for collagen, heparin and cell surface receptors, especially integrins,
and so can promote adhesion between all these elements. In connective
tissues, the molecules are able to bind to cell surfaces in an orderly
fashion, to form short fibronectin filaments. The liver secretes a related
protein, plasma fibronectin, into the circulation. The selective adhesion
of different cell types to the matrix during development and in postna -
tal life is mediated by numerous isoforms of fibronectin generated by alternative splicing. Isoforms found in embryonic tissues are also
expressed during wound repair, when they facilitate tissue proliferation
and cell movements; the adult form is re-expressed once repair is
complete.
laminin
Laminin is a large (850 kDa) flexible molecule composed of three
polypeptide chains (designated α, β and γ). There are many isoforms
of the different chains, and at least 18 types of laminin. The prototypical
molecule has a cruciform shape, in which the terminal two-thirds are
wound round each other to form the stem of a cross, and the shorter free ends form the upright and transverse members. Laminin bears binding sites for other extracellular matrix molecules such as heparan sulphate, type IV collagen and entactin, and also for laminin receptor molecules (integrins) situated in cell plasma membranes. Laminin mol -
ecules can assemble themselves into flat regular meshworks, e.g. in the basal lamina. | 83 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
INTE gRATIN g CEllS INTO TISS uES
40 SECTION 1
foci of stratified squamous metaplasia in response to irritants in ciga -
rette smoke. Mesenchymal (osseous) metaplasia can occur, for example,
in the fibrous connective tissue of muscles subjected to repeated
damage, where trabeculi of bone develop. It is thought that stem cells
(rather than the differentiated cells) in the affected tissue respond to
changes in their environment by altering their differentiation pathway,
a process that may be reversible if the stimulus is removed.
MUCOSA (MUCOUS MEMBRANE)
A mucosa or mucous membrane ( Fig 2.16) lines many internal hollow
organs in which the inner surfaces are moistened by mucus, such as the intestines, conducting portions of the airway, and the genital and
urinary tracts. A mucosa proper consists of an epithelial lining, which
may have the ducts of mucosal, submucosal or extrinsic glands opening
on to its surface, an underlying loose connective tissue, the lamina
propria, and a thin layer of smooth muscle, the muscularis mucosae.
This last layer either may be absent from some mucosae, or may be
replaced by a layer of elastic fibres. The term mucous membrane reflects
the fact that these tissues can all be peeled away as a sheet or membrane
from underlying structures; the plane of separation occurs along the
muscularis mucosae.
Submucosa is a layer of supporting connective tissue that usually lies
below the muscularis mucosae. It may contain mucous or seromucous
submucosal glands. Inflammation of the viscera involves, primarily, the
connective tissues of the submucosa and lamina propria, and is char -
acterised by dilated vessels, oedema, and accumulations of extravasated immune defence cells. Most mucosae are also supported by one or more
layers of smooth muscle, the muscularis externa. Contraction of this
muscle may constrict the mucosal lumen (e.g. in the airway) or, where
there are two or more muscle layers orientated in opposing directions
(e.g. in the intestines), cause peristaltic movement of the viscus and the
contents of its lumen. The outer surface of the muscle may be covered
by a serosa or, where the structure is retroperitoneal or passes through
the pelvic floor, by a connective tissue adventitia.
MUCUS
Mucus is a viscous suspension of complex glycoproteins (mucins) of various kinds, and is secreted by scattered individual epithelial (goblet)
cells, a secretory surface epithelium (e.g. the stomach lining) or mucous
and seromucous glands. The precise composition of the mucus varies
with the tissue and secretory cells that produce it. All mucins consist of
filamentous core proteins to which are attached carbohydrate chains, usually branched; salivary mucus contains nearly 600 chains. Carbohy -
drate residues include glucose, fucose, galactose and N-acetylglucosamine
(sialic acid). The terminals of some carbohydrate chains are identical to the blood group antigens of the ABO group in the majority of the population (secretors, bearing the secretor gene S
e), and can be detected
in salivary mucus by means of appropriate clinical tests. The long poly -
meric carbohydrate chains bind water and protect surfaces against Regular connective tissues
Regular connective tissues include highly fibrous tissues in which fibres
are regularly orientated, either to form sheets such as fasciae and
aponeuroses, or as thicker bundles such as ligaments or tendons ( Fig.
2.15). The direction of the fibres within these structures is related to
the stresses that they undergo: fibrous bundles display considerable
interweaving, even within tendons, which increases their structural sta -
bility and resilience.
The fibroblasts that secrete the fibres may eventually become trapped
within the fibrous structure, where they become compressed, relatively inactive cells with stellate profiles and small heterochromatic nuclei;
these cells are called tendon cells. Fibroblasts on the external surface
may be active in continued fibre formation and they constitute a pool
of cells available for repair of injured tissue.
Although regular connective tissue is predominantly collagenous,
some ligaments contain significant amounts of elastin, e.g. the liga -
menta flava of the vertebral laminae and the vocal folds. The collagen fibres may form precise geometrical patterns, as in the cornea.
Mucoid tissue
Mucoid tissue is found chiefly as a stage in the development of connec -
tive tissue from mesenchyme. It exists in Wharton’s jelly, which forms
the bulk of the umbilical cord, and consists substantially of extracellular
matrix, largely made up of hydrated mucoid material and a fine mesh -
work of collagen fibres, in which nucleated, fibroblast-like cells with branching processes are found. Fibres are usually rare in typical mucoid
tissue, although the full-term umbilical cord contains perivascular col -
lagen fibres. Postnatally, mucoid tissue is seen in the pulp of a develop -
ing tooth, the vitreous body of the eye (a persistent form of mucoid
tissue that contains few fibres or cells) and the nucleus pulposus of the
intervertebral disc.
TRANSDIFFERENTIATION AND METAPLASIA
Transitions occur between populations of cells forming an epithelium (sheets of polarized cells) and mesenchymal types (where the cells lack
polarity) during normal development (see Thiery et al (2009)). In post -
natal life, most well-described transitions between morphologically dif -
ferent cell types do not cross an epithelial–mesenchymal boundary but are transitions between types of epithelial cell or, less frequently,
between mesenchymal (connective tissue) cell types. Most instances
of such transdifferentiation (metaplasia, see Commentary 1.4) are
adaptive, to changing environmental conditions or trauma, and almost
all are pathological; the altered cells are termed metaplastic. A very
common and physiologically normal example is the squamous meta -
plasia of columnar secretory epithelium of the distal endocervical canal,
when exposed to the hormonally stimulated vaginal environment. Gastric metaplasia of the lower oesophagus may occur when chronic reflux of gastric juices exposes its stratified squamous epithelial lining to acid, and the original epithelium is replaced by a mucus-secreting columnar epithelium typical of the stomach (Barrett’s oesophagus); this is pathological and susceptible to malignant change. Similarly, the res -
piratory epithelium (see Fig. 2.2D) of the upper airway often develops
Fig. 2.15 Dense regular connective tissue in a tendon. Thick parallel
bundles of type I collagen (here stained pink) give tendon its white colour
in life. The elongated nuclei of inactive fibroblasts (tendon cells) are visible
between collagen bundles.
Fig. 2.16 A generalized mucosa and supporting tissues. For details and
variations, see text. Mucosa
SubmucosaEpithelium
Lamina propria
Muscularis mucosae
Muscularis
externa
Submucosal glandDuct of extrinsic
gland or organSerosa | 84 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
41
CHAPTER 2Key references
FASCIA
Fascia is a generic term applied to sheaths, sheets or other dissectible
masses of connective tissue that are large enough to be visible to the unaided eye. The terms superficial fascia and deep fascia, widely used to describe the connective tissue between the skin and underlying muscle, and the connective tissue surrounding muscles, viscera and
related structures, respectively, are no longer included in the Terminolo-
gia Anatomica, although they remain in common usage in the English
language. Tela subcutanea, hypodermis and subcutaneous tissue are
the recommended synonymous terms that replace superficial fascia. Deeper-lying condensations of connective tissue have been defined according to their location, e.g. investing muscles (fascia musculorum) or viscera (fascia visceralis). Loosely packed connective tissue surrounds peripheral nerves, blood and lymph vessels as they pass between
other structures, often linking them together as neurovascular bundles. Some large vessels, e.g. the common carotid and femoral arteries, are invested by a dense connective tissue sheath that may be functionally significant, aiding venous return by approximating large veins to pulsat -
ing arteries.drying; they also provide good lubricating properties. In concentrated form, mucins form viscous layers that protect the underlying tissues against damage.
Synthesis of mucus starts in the rough endoplasmic reticulum. It is
then passed to the Golgi complex, where it is conjugated with sulphated
carbohydrates to form the glycoprotein, mucinogen, and this is exported
in small, dense, membrane-bound vesicles that swell as they approach the cell surface, with which they fuse before releasing their contents.
SEROSA (SEROUS MEMBRANE)
Serosa consists of a single layer of squamous mesothelial cells, express -
ing keratin intermediate filaments, supported by an underlying layer of loose connective tissue that contains numerous blood and lymphatic vessels. Serosa lines the pleural, pericardial and peritoneal cavities, and covers the external surfaces of organs lying within those cavities and, in
the abdomen, the mesenteries that envelop them. A potential space,
filled with a small amount of protein-containing serous fluid – largely an exudate of interstitial fluid – exists between the outer parietal and the inner visceral layers of the serosa.
KEY REFERENCES
Collington SJ, Williams TJ, Weller CL 201 1 Innate immune cell trafficking:
mechanisms underlying the localisation of mast cells in tissues. Trends
Immunol 32:478–85.A discussion of recent advances in understanding the recruitment of mast cells to tissues.
Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat
Med 18:1 178–80.A review of recent evidence for a perivascular cell (pericyte) origin for myofibroblasts and fibrotic tissue in a number of disease states.
Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine
80:141–5.
A description of the role of mast cells in inflammatory processes and
prospects for therapeutic intervention in inflammatory diseases.
Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev
Cardiol 9:689–702.
A review of the status of adipose tissue, its structural and functional variations and roles in health and disease.
Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi -
broblast biology. Am J Path 180:1340–55.
A review of recent work on myofibroblasts, their origins, molecular
regulation of differentiation from precursor cells and roles in organ-specific
fibrotic disease processes.
McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and
role in disease. Int J Biochem Cell Biol 39:666–71.A review of the biology of connective tissue fibroblasts and related
mesenchymal cells.
Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
intermediate filaments in normal and diseased epithelia. Curr Opin Cell Biol 25:1–10.A discussion of the current understanding of the keratin intermediate filament family, specific to epithelia, and the roles of keratins in epithelial functions and selected diseases.
Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed.
Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules, pp. 531–52.A comprehensive text on the molecular structures and functions of matrix molecules.
Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi -
tions in development and disease. Cell 139:871–90.A description of these processes in normal development and the contribution of epithelial–mesenchymal transitions to carcinoma progression and metastasis.
Wolf K, Friedl P 201 1 Extracellular matrix determinants of proteolytic and
non-proteolytic cell migration. Trends Cell Biol 21:736–44.A review of cell migration through extracellular matrices in wound healing and pathological processes, using proteolytic and other mechanisms. | 85 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Integrating cells into tissues
41.e1
CHAPTER 2
REFERENCES
Ankrum J, Karp JM 2010 Mesenchymal stem cell therapy: two steps forward,
one step back. Trends in Mol Med 16:203–9.
Bischoff SC 2007 Role of mast cells in allergic and non-allergic immune
responses: comparison of human and murine data. Nat Rev Immunol
7:93–104.
Blanpain C, Horsley V, Fuchs E 2007 Epithelial stem cells: turning over new
leaves. Cell 128:445–8.
Collington SJ, Williams TJ, Weller CL 201 1 Innate immune cell trafficking:
mechanisms underlying the localisation of mast cells in tissues. Trends Immunol 32:478–85.A discussion of recent advances in understanding the recruitment of mast cells to tissues.
Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat
Med 18:1 178–80.
A review of recent evidence for a perivascular cell (pericyte) origin for
myofibroblasts and fibrotic tissue in a number of disease states.
Even-Ram S, Yamada KM 2005 Cell migration in 3D matrix. Curr Opin Cell
Biol 17:524–32.
Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine
80:141–5.A description of the role of mast cells in inflammatory processes and
prospects for therapeutic intervention in inflammatory diseases.
Gaide Chevronnay HP, Selvais C, Emonard H et al 2012 Regulation of matrix
metalloproteinases activity studied in human endometrium as a para -
digm of cyclic tissue breakdown and regeneration. Biochim Biophys
Acta 1824:146–56.
Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev
Cardiol 9:689–702.A review of the status of adipose tissue, its structural and functional variations and roles in health and disease.
Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi -
broblast biology. Am J Path 180:1340–55.A review of recent work on myofibroblasts, their origins, molecular regulation of differentiation from precursor cells and roles in organ-specific fibrotic disease processes.
Iozzo RV 2005 Basement membrane proteoglycans: from cellar to ceiling.
Nat Rev Mol Cell Biol 6:646–56.
Jackson WM, Nesti LJ, Tuan RS 2012 Concise review: clinical translation of
wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med 1:44–50.Jacquemet G, Humphries MJ, Caswell PT 2013 Role of adhesion receptor
trafficking in 3D cell migration. Curr Opin Cell Biol 25:1–6.
McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and
role in disease. Int J Biochem Cell Biol 39:666–71.A review of the biology of connective tissue fibroblasts and related mesenchymal cells.
Mott JD, Werb Z 2004 Regulation of matrix biology by matrix metallopro -
teinases. Curr Opin Cell Biol 16:558–64.
Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
intermediate filaments in normal and diseased epithelia. Curr Opin Cell Biol 25:1–10.A discussion of the current understanding of the keratin intermediate filament family, specific to epithelia, and the roles of keratins in epithelial functions and selected diseases.
Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed.
Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules, pp. 531–52.A comprehensive text on the molecular structures and functions of matrix molecules.
Ren G, Chen X, Dong F et al 2012 Concise review: mesenchymal stem cells
and translational medicine: emerging issues. Stem Cells Transl Med 1:51–8.
Stoeckelhuber M, Schubert C, Kesting MR et al 201 1 Human axillary apo -
crine glands: proteins involved in the apocrine secretory mechanism. Histol Histopathol 26:177–84.
Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi -
tions in development and disease. Cell 139:871–90.A description of these processes in normal development and the contribution of epithelial–mesenchymal transitions to carcinoma progression and metastasis.
Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic
role of white adipose tissue. Br J Nutr 92:347–55.
Wolf K, Friedl P 201 1 Extracellular matrix determinants of proteolytic and
non-proteolytic cell migration. Trends Cell Biol 21:736–44.A review of cell migration through extracellular matrices in wound healing and pathological processes, using proteolytic and other mechanisms.
Wu J, Bostro P, Sparks LM et al 2012 Beige adipocytes are a distinct type of
thermogenic fat cell in mouse and human. Cell 150:366–76. | 86 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
42 SECTION 1
CHAPTER 3 Nervous system
with neurones in many different ways; their two-way communication
is essential for normal brain activity.
It was thought for many years that glia outnumbered neurones by
10 times in the CNS, but recent studies using the isotropic fractionator method have challenged that popular view, suggesting instead that the
two cell populations are rather similar in size (Azevedo et al 2009). That
said, the glia : neurone ratio has been reported to be as high as 17 : 1 in
the thalamus (Pakkenberg and Gundersen 1988).
The glial population in the CNS consists of microglia and macroglia;
the latter are subdivided into oligodendrocytes and astrocytes. The principal glial cell in the PNS is the Schwann cell. Satellite cells sur -
round each neuronal soma in ganglia.
For further reading on the nervous system, see Finger (2001), Kandel
et al (2012), Kettenmann and Ransom (2012), Levitan and Kaczmarek
(2001), Nicholls et al (201 1) and Squire et al (2012).
NEURONES
Most of the neurones in the CNS are either clustered into nuclei,
columns or layers, or dispersed within grey matter. Neurones in the PNS
are confined to ganglia. Irrespective of location, neurones share many
general features, which are discussed here in the context of central
neurones. Special characteristics of ganglionic neurones and their adja-
cent tissues are discussed on page 57.
Neurones exhibit great variability in their size (cell bodies range
from 5 to 100 µm diameter) and shape (Spruston 2008). Their surface
areas are extensive because most neurones display numerous branched
cell processes. They usually have a rounded or polygonal cell body
(perikaryon or soma). This is a central mass of cytoplasm that encloses
a nucleus and gives off long, branched extensions with which most
intercellular contacts are made. Typically, one of these processes, the
axon, is much longer than the others, the dendrites ( Fig. 3.2). Gener-
ally, dendrites conduct electrical signals towards a soma whereas axons conduct impulses away from it.
Neurones can be classified according to the number and arrange -
ment of their processes (Bota and Swanson 2007). Multipolar neurones
(Fig. 3.3) are common; they have an extensive dendritic tree that arises
either from a single primary dendrite or directly from the soma, and a
single axon. Bipolar neurones, which typify neurones of the special
sensory systems, have only a single dendrite that emerges from the soma
opposite the axonal pole. Unipolar neurones, which transmit general
sensation, e.g. dorsal root ganglion neurones, have a single short process
that bifurcates into a peripheral and a central process. This arrangement
arises by the fusion of the proximal axonal and dendritic processes of
a bipolar neurone during development, and so such neurones may also
be termed pseudounipolar. Neurones may also be classified according
to whether their axons terminate locally on other neurones (interneu -
rones), or transmit impulses over long distances, often to distinct ter -
ritories via defined tracts (projection neurones).
Neurones are postmitotic cells and, with few exceptions, they are not
replaced when lost.
SOMA
The plasma membrane of the soma is generally unmyelinated and
is contacted by both inhibitory and excitatory axosomatic synapses;
very occasionally, somasomatic and dendrosomatic contacts may be
made. The non-synaptic surface may contain gap junctions and is partly covered by either astrocytic or satellite oligodendrocyte processes.
The cytoplasm of a typical soma (see Fig. 3.2) is rich in rough and
smooth endoplasmic reticulum and free polyribosomes, indicating
a high level of protein synthetic activity. Free polyribosomes often The nervous system has two major divisions, the central nervous system
(CNS) and the peripheral nervous system (PNS). The CNS consists of
the brain, spinal cord, optic nerve and retina, and contains the majority
of neuronal cell bodies. The PNS includes all nervous tissue outside the
CNS and consists of the cranial and spinal nerves, the peripheral auto -
nomic nervous system (ANS) and the special senses (taste, olfaction, vision, hearing and balance). It is composed mainly of the axons of
sensory and motor neurones that pass between the CNS and the body.
The ANS is subdivided into sympathetic and parasympathetic compo -
nents. It consists of neurones that innervate secretory glands and cardiac and smooth muscle, and is concerned primarily with control of the
internal environment. Neurones in the wall of the gastrointestinal tract
form the enteric nervous system (ENS) and are capable of sustaining
local reflex activity that is independent of the CNS. The ENS contains
as many intrinsic neurones in its ganglia as the entire spinal cord and
is often considered as a third division of the nervous system (Gershon
1998).
In the CNS, the cell bodies of neurones are often grouped together
in discrete areas termed nuclei, or they may form more extensive layers
or masses of cells; collectively they constitute the grey matter. Neuronal
dendrites and synaptic contacts are mostly confined to areas of grey
matter and form part of its meshwork of neuronal and glial processes,
termed the neuropil. Their axons join bundles of nerve fibres that tend
to be grouped separately to form tracts. In the spinal cord, cerebellum,
cerebral cortices and some other areas, concentrations of tracts consti -
tute the white matter, so called because the axons are often ensheathed in lipid-rich sheaths of myelin, which is white when fresh ( Fig. 3.1; see
Fig. 16.9).
The PNS is composed of the efferent axons (fibres) of motor neu -
rones situated inside the CNS, and the cell bodies of sensory neurones (grouped together as ganglia) and their afferent processes. Sensory cells
in dorsal root ganglia give off both centrally and peripherally directed
processes; there are no synapses on their cell bodies. Also included are
ganglionic neurones of the ANS, which receive synaptic contacts from
the peripheral fibres of preganglionic autonomic neurones whose cell
bodies lie within the CNS. For further details of the organization of the
nervous system, see Chapter 16.
When the neural tube is formed during prenatal development (Sanes
et al 201 1), its walls thicken greatly but do not completely obliterate
the cavity within. The latter remains in the spinal cord as the narrow
central canal and becomes greatly expanded in the brain to form a series
of interconnected cavities called the ventricular system. In the fore- and
hindbrains, parts of the neural tube roof do not generate neurones but
become thin, folded sheets of secretory tissue, which are invaded by
blood vessels and are called the choroid plexuses. The latter secrete
cerebrospinal fluid (CSF), which fills the ventricles and subarachnoid
spaces, and penetrates the intercellular spaces of the brain and spinal
cord to create their interstitial fluid. The CNS has a rich blood supply,
which is essential to sustain its high metabolic rate. The blood–brain
barrier places considerable restrictions on the substances that are able
to diffuse from the blood stream into the neuropil.
Neurones encode information, conduct it over considerable dis-
tances, and then transmit it to other neurones or to various non-neural
targets such as muscle cells. The propagation of this information within
the nervous system depends on rapid electrical signals, the action
potentials. Transmission to other cells is mediated by secretion of neu -
rotransmitters at special junctions, either with other neurones (syn -
apses), or with cells outside the nervous system, e.g. muscle cells at
neuromuscular junctions, gland cells or adipose tissue, and causes changes in the behaviour of the target cells.
The nervous system contains large populations of non-neuronal
cells, termed neuroglia or glia. These cells do not generate action poten -
tials, but convey information encoded as transient changes in intracel-lular calcium concentration, termed calcium signalling. Glia interact
| 87 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Nervous system
42.e1
CHAPTER 3
Fig. 3.1 A section through the human cerebellum stained to show the
arrangement in the brain of the central white matter (WM, deep pink) and
the highly folded outer grey matter (GM). In the cerebellum, GM consists of an inner granular layer of tightly packed small neurones (blue) and an outermost molecular layer (pale pink), where neuronal processes make
synaptic contacts. (Courtesy of Mr Peter Helliwell and the late Dr Joseph
Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
WM
GM | 88 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Neurones
43
CHAPTER 3
tide subunits, NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa).
NF-M and NF-H have long C-terminal domains that project as side arms
from the assembled neurofilament and bind to neighbouring filaments.
They can be heavily phosphorylated, particularly in the highly stable
neurofilaments of mature axons, and are thought to give axons their
tensile strength. Some axons are almost filled by neurofilaments.
Microtubules are important in axonal transport, although dendrites
usually have more microtubules than axons. Centrioles persist in
mature postmitotic neurones, where they are concerned with the gen -
eration of microtubules rather than cell division. Centrioles are associ -
ated with cilia on the surfaces of developing neuroblasts. Their
significance, other than at some sensory endings (e.g. the olfactory
mucosa), is not known.
Pigment granules ( Fig. 3.5) appear in certain regions, e.g. neurones
of the substantia nigra contain neuromelanin, which is probably a
waste product of catecholamine synthesis. A similar pigment gives a
bluish colour to the neurones in the locus coeruleus. Some neurones
are unusually rich in metals, which may form components of enzyme
systems, e.g. zinc in the hippocampus and iron in the red nucleus.
Ageing neurones, especially in spinal ganglia, accumulate granules of
lipofuscin (senility pigment) in residual bodies, which are lysosomes
packed with partially degraded lipoprotein material.
DENDRITES
Dendrites are highly branched, usually short processes that project from
the soma (see Fig. 3.2; Shah et al 2010). The branching patterns of many
dendritic arrays are probably established by random adhesive interac -
tions between dendritic growth cones and afferent axons that occur during development. There is an overproduction of dendrites in early
development, and this is pruned in response to functional demand as
the nervous system matures and information is processed through the
dendritic tree. There is evidence that dendritic trees may be plastic
structures throughout adult life, expanding and contracting as the traffic
of synaptic activity varies through afferent axodendritic contacts (for a
review, see Wong and Ghosh (2002)). Groups of neurones with similar
functions have a similar stereotypic tree structure ( Fig. 3.6), suggesting
that the branching patterns of dendrites are important determinants of
the integration of the afferent inputs that converge on the tree. For a
review of current research on dendritic trees in the normal and patho -
logical brain, see Kulkarni and Firestein (2012).
Dendrites differ from axons in many respects. They represent the
afferent rather than the efferent system of the neurone, and receive both excitatory and inhibitory axodendritic contacts. They may also make
dendrodendritic and dendrosomatic connections (see Fig. 3.9), some
of which are reciprocal. Synapses occur either on small projections called dendritic spines or on the smooth dendritic surface. Dendrites
contain ribosomes, smooth endoplasmic reticulum, microtubules, neu -
rofilaments, actin filaments and Golgi complexes. Their neurofilament proteins are poorly phosphorylated and their microtubules express the
microtubule-associated protein (MAP)-2 almost exclusively in compari-
son with axons.
The shapes of dendritic spines range from simple protrusions to
structures with a slender stalk and expanded distal end. Most spines are
not more than 2 µm long, and have one or more terminal expansions;
they can also be short and stubby, branched or bulbous. Large mush -
room spines are assumed to have differentiated in response to afferent
activity (‘memory spines’; Matsuzaki et al 2004). These large spines
often contain a spine apparatus, an organelle consisting of small
sacs of endoplasmic reticulum interleaved by electron-dense bars (Gray
1959, Segal et al 2010). Mouse mutants deficient in these organelles
show memory deficits (Deller et al 2003). Free ribosomes and polyri -
bosomes are concentrated at the base of the spine. Ribosomal accumu -
lations near synaptic sites provide a mechanism for activity-dependent
synaptic plasticity through the local regulation of protein synthesis.
AXONS
The axon originates either from the soma or from the proximal segment
of a dendrite at a specialized region free of Nissl granules, the axon
hillock (see Fig. 3.2). Action potentials are initiated here, at the junction
with the proximal axon (axon initial segment). The axonal plasma membrane (axolemma) is undercoated at the hillock by a concentration of cytoskeletal molecules, including spectrin and actin fibrils, which are important in anchoring numerous voltage-sensitive channels to the membrane. For details, see Bender and Trussell (2012), and for neural
electrophysiological techniques, see Sakmann and Neher (2009). The congregate in large groups associated with the rough endoplasmic retic -
ulum. These aggregates of RNA-rich structures are visible by light micro -
scopy as basophilic Nissl bodies or granules. They are distributed
throughout the cell body and large dendrites; the axon hillock is con -
spicuously ribosome-free. Nissl bodies are more obvious in large, highly active cells, such as spinal motor neurones (Fig. 3.4), which contain
large stacks of rough endoplasmic reticulum and polyribosome aggre -
gates. Maintenance and turnover of cytoplasmic and membranous com-ponents are necessary activities in all cells; the huge total volume of
cytoplasm within the soma and processes of many neurones requires a
considerable commitment of protein synthetic machinery. Neurones
also synthesize other proteins (enzyme systems, G-protein coupled
receptors, scaffold proteins) involved in the production of neurotrans -
mitters and in the reception and transduction of incoming stimuli. Various transmembrane channel proteins and enzymes are located at
the surfaces of neurones, where they are associated with movements
of ions.
The nucleus is characteristically large and euchromatic, and contains
at least one prominent nucleolus; these are features typical of all cells engaged in substantial levels of protein synthesis. The cytoplasm con -
tains many mitochondria and moderate numbers of lysosomes. Golgi complexes are usually close to the nucleus, near the bases of the main
dendrites and opposite the axon hillock.
The neuronal cytoskeleton is a prominent feature of its cytoplasm
and gives shape, strength and support to the dendrites and axons. A
number of neurodegenerative diseases are characterized by abnormal
aggregates of cytoskeletal proteins (reviewed in Cairns et al (2004)).
Neurofilaments (the intermediate filaments of neurones) and microtu -
bules are abundant in the soma and along dendrites and axons; the
proportions vary with the type of neurone and cell process. Bundles of neurofilaments constitute neurofibrils, which can be seen by light microscopy in silver-stained or immunolabelled sections. Neurofila -
ments are heteropolymers of proteins assembled from three polypep-Fig. 3.2 A schematic view of typical neurones featuring one with the
soma cut away to show the nucleus and cytoplasmic organelles, dendritic
trees with synaptic contacts, other types of synapse, the axon hillock and
a myelinated axon. Soma
Nucleolus
Nucleus
Axon hillock
Dendrite
Axon
Myelin sheath
Axon collateral
Axo-axonal
synapseAxodendritic
synapse
Axosomatic
synapse
Synaptic
terminals | 89 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
44 SECTION 1
Fig. 3.5 Neurones in
the substantia nigra of
the human midbrain, showing cytoplasmic granules of
neuromelanin pigment.
(Courtesy of Mr Peter Helliwell and the late
Dr Joseph Mathew, Department of Histopathology, Royal
Cornwall Hospitals
Trust, UK.)
Fig. 3.3 The variety of shapes of neurones and their processes. The inset shows a human multipolar retinal ganglion cell, filled with fluorescent dye by
microinjection. (Inset, Courtesy of Drs Richard Wingate, James Morgan and Ian Thompson, King’s College, London.)
Smooth muscle
e.g intestine
Striated (skeletal)
muscleUnipolar
neurone
Peripheral
axonSensory endings
e.g. in skin
Bipolar
neurone
Soma
Axon
Soma
Central
axonSensory Integrative Motor
Apical
dendrites
Pyramidal cell
soma
Axon
Interneurone
AxonSomaBasal
dendrites
AxonDendrites
Purkinje cell
soma
AxonNissl bodies
in soma
SomaLarge motorneurone
AxonPresynaptic
autonomic
neurone
Soma
Postsynaptic
autonomic
neuroneAxon
Interneurone
Fig. 3.4 Spinal motor neurones (toluidine blue stained resin section, rat
tissue) showing a group of cell bodies (somata, S), some with the
proximal parts of axonal and dendritic processes (P) visible. Their nuclei (N) typically have prominent, deeply staining nucleoli, indicative of metabolically highly active cells; two are visible in the plane of section.
Nissl granules (G) are seen in the cytoplasm. Surrounding the neuronal
somata is the neuropil, consisting of the interwoven processes of these and other neurones and of glial cells.
S
GN
P
P | 90 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Neurones
45
CHAPTER 3
role in Alzheimer’s disease (Cairns et al 2004): formation of tau oli -
gomers and the subsequent pathological filament arrays are critical
steps in the aetiopathogenesis of this condition. Neurofilament proteins
ranging from high to low molecular weights are highly phosphorylated
in mature axons, whereas growing and regenerating axons express a
calmodulin-binding membrane-associated phosphoprotein, growth-
associated protein-43 (GAP-43), as well as poorly phosphorylated
neurofilaments.
Neurones respond differently to injury, depending on whether the
damage occurs in the CNS or the PNS. The glial microenvironment of
a damaged central axon does not facilitate axonal regrowth; conse -
quently, reconnection with original synaptic targets does not normally occur. In marked contrast, the glial microenvironment in the PNS is
capable of facilitating axonal regrowth. However, functional outcome
of clinical repair of a large mixed peripheral nerve, especially if the
injury occurs some distance from the target organ, or produces a long
defect in the damaged nerve, is frequently unsatisfactory (Birch 201 1;
see also Commentary 1.6 ).
Axoplasmic flow
Neuronal organelles and cytoplasm are in continual motion. Bidirec -
tional streaming of vesicles along axons results in a net transport of
materials from the soma to the terminals, with more limited movement
in the opposite direction. Two major types of transport occur, one slow
and one relatively fast. Slow axonal transport is a bulk flow of axoplasm
only in the anterograde direction, carrying cytoskeletal proteins and
soluble, non-membrane-bound proteins from the soma to the termi -
nals at a rate of approximately 0.1–3 mm a day. In contrast, fast axonal
transport carries membrane-bound vesicular material (endosomes and
lysosomal autophagic vacuoles) and mitochondria at approximately
200 mm a day in the retrograde direction (towards the soma) and
approximately 40 mm per day anterogradely (in particular, synaptic
vesicles containing neurotransmitters).
Rapid flow depends on microtubules. Vesicles with side projections
line up along microtubules and are transported along them by their side arms. Two microtubule-based motor proteins with adenosine 5 ′-
triphosphatase (ATPase) activity are involved in fast transport: kinesin family proteins are responsible for the fast component of anterograde
transport, and cytoplasmic dynein is responsible for retrograde trans -
port. Retrograde transport mediates the movement of neurotrophic viruses, e.g. herpes zoster, rabies and polio, from peripheral terminals,
and their subsequent concentration in the neuronal soma. It has been
suggested that specific pools of endocytic organelles, signalling endo -
somes, mediate the long-distance axonal transport of growth factors, such as neurotrophins and their signalling receptors. Defects in axonal
and dendritic transport have been linked to various neurodegenerative
processes. See Guzik and Goldstein (2004), Hinckelmann et al (2013)
and Schmieg et al (2014) for reviews of axonal transport in health and
disease.
SYNAPSES
Transmission of impulses across specialized junctions (synapses) between two neurones is largely chemical and depends on the release
of neurotransmitters from the presynaptic terminal. These neurotrans -
mitters bind to cognate receptors in the postsynaptic neuronal mem -
brane, resulting in a change of membrane conductance and leading to
either a depolarization or a hyperpolarization (Ryan and Grant 2009).
The patterns of axonal termination vary considerably. A single axon
may synapse with one neurone (e.g. climbing fibres ending on cere -
bellar Purkinje neurones), or more often with many neurones (e.g. cerebellar parallel fibres, which provide an extreme example of this
phenomenon). In synaptic glomeruli (e.g. in the olfactory bulb), groups
of synapses between two or many neurones form interactive units
encapsulated by neuroglia ( Fig. 3.7
; Perea et al 2009).
Electrical synapses (direct communication via gap junctions) are rare
in the human CNS and are confined largely to groups of neurones with tightly coupled activity, e.g. the inspiratory centre in the medulla. They
will not be discussed further here.
Classification of chemical synapses
Chemical synapses have an asymmetric structural organization ( Figs
3.8–3.9) in keeping with the unidirectional nature of their transmis-
sion. Typical chemical synapses share a number of important features. They all display an area containing a presynaptic density apposed to a
axon hillock is unmyelinated and often participates in inhibitory axo-
axonal synapses. It is unique because it contains ribosomal aggregates
immediately below the postsynaptic membrane (Kole and Stuart 2012).
In the CNS, small, unmyelinated axons lie free in the neuropil,
whereas in the PNS they are embedded in Schwann cell cytoplasm.
Myelin, which is formed around almost all axons of >2 µm diameter
by oligodendrocytes in the CNS and by Schwann cells in the PNS, begins at the distal end of the axon hillock. Nodes of Ranvier are spe -
cialized regions of myelin-free axon where action potentials are gener -
ated and where an axon may branch. In both CNS and PNS, the territory
of a myelinated axon between adjacent nodes is called an internode;
the region close to a node, where the myelin sheath terminates, is called
the paranode; and the region just beyond that is the juxtaparanode.
Myelin thickness and internodal lengths are, in general, positively cor -
related with axon diameter. The density of sodium channels in the axolemma is highest at nodes of Ranvier, and very low along internodal
membranes; sodium channels are spread more evenly within the axo -
lemma of unmyelinated axons. Fast potassium channels are present in the paranodal regions of myelinated axons. Fine processes of glial cyto-
plasm (astrocytic in the CNS, Schwann cell in the PNS) surround the
nodal axolemma.
The terminals of an axon are unmyelinated. Most expand into presy-
naptic boutons, which may form connections with axons, dendrites,
neuronal somata or, in the periphery, muscle fibres, glands and lym -
phoid tissue. Exceptions include the free afferent sensory endings in, for example, the epidermis, which are unspecialized structurally, and
the peripheral terminals of afferent sensory fibres with encapsulated
endings (see Fig. 3.27). Axon terminals contain abundant small clear
synaptic vesicles and large dense-core vesicles. The former contain a neurotransmitter (e.g. glutamate, γ-aminobutyric acid (GABA), acetyl -
choline) that is released into the synaptic cleft on the arrival of an action potential at the terminal and which then binds to cognate receptors on
the postsynaptic membrane. Depending on the nature of the transmit -
ter and its receptors, the postsynaptic neurone will become excited or inhibited. The dense-core vesicles contain neuropeptides, including
brain-derived neurotrophic factor (BDNF; Dieni et al 2012). Axon ter -
minals may themselves be contacted by other axons, forming axo-
axonal presynaptic inhibitory circuits. Further details of neuronal
microcircuitry are given in Kandel et al (2012) and Haines (2006).
Axons contain microtubules, neurofilaments, mitochondria, mem -
brane vesicles, cisternae and lysosomes. They do not usually contain ribosomes or Golgi complexes, other than at the axon hillock; excep -
tionally, the neurosecretory fibres of hypothalamo-hypophysial neu -
rones contain the mRNA of neuropeptides. Organelles are differentially
distributed along axons, e.g. there is a greater density of mitochondria and membrane vesicles in the axon hillock, at nodes and in presynaptic endings. Axonal microtubules are interconnected by cross-linking MAPs, of which tau is the most abundant. Microtubules have an intrin -
sic polarity, and in axons all microtubules are uniformly orientated with their rapidly growing ends directed away from the soma towards the axon terminal. The microtubule binding protein tau plays an important
Fig. 3.6 A Purkinje
neurone from the
cerebellum of a rat
stained by the
Golgi–Cox method,
showing the extensive
two-dimensional array
of dendrites. (Courtesy
of Dr Martin Sadler and
Professor M Berry,
Division of Anatomy
and Cell Biology, GKT
School of Medicine,
London.) | 91 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
46 SECTION 1
corresponding postsynaptic density; the two are separated by a narrow
(20–30 nm) gap, the synaptic cleft. Synaptic vesicles containing the
appropriate neurotransmitter are found on the presynaptic side, clus -
tered near the presynaptic density at the presynaptic membrane.
Together these define the active zone, the area of the synapse where
neurotransmission takes place (Eggermann et al 2012, Gray 1959).
Chemical synapses can be classified according to a number of dif-
ferent parameters, including the neuronal regions forming the synapse, their ultrastructural characteristics, the chemical nature of their
neurotransmitter(s) and their effects on the electrical state of the post -
synaptic neurone. The following classification is limited to associations between neurones. Neuromuscular junctions share many (though not
all) of these parameters, and are often referred to as peripheral synapses.
They are described separately on page 63.
Synapses can occur between almost any surface regions of the par-
ticipating neurones. The most common type occurs between an axon
and either a dendrite or a soma, when the axon is expanded as a small
bulb or bouton (see Figs 3.8–3.9). This may be a terminal of an axonal
branch (terminal bouton) or one of a row of bead-like endings, when the axon makes contact at several points, often with more than one
neurone (bouton de passage). Boutons may synapse with dendrites,
including thorny protrusions named dendritic spines or the flat surface
of a dendritic shaft; a soma (usually on its flat surface, but occasionally
on spines); the axon hillock; and the terminal boutons of other axons.
The connection is classified according to the direction of transmis -
sion, and the incoming terminal region is named first. Most common
are axodendritic synapses, although axosomatic connections are fre -
quent. All other possible combinations are found but are less common, i.e. axo-axonal, dendro-axonal, dendrodendritic, somatodendritic or
somatosomatic. Axodendritic and axosomatic synapses occur in all
regions of the CNS and in autonomic ganglia, including those of
the ENS. The other types appear restricted to regions of complex inter -
action between larger sensory neurones and microneurones, e.g. in the
thalamus.
Ultrastructurally, synaptic vesicles may be internally clear or dense,
and of different size (loosely categorized as small or large) and shape
(round, flat or pleomorphic, i.e. irregularly shaped). The submembra -
nous densities may be thicker on the postsynaptic than on the presyn -
aptic side (asymmetric synapses), or equivalent in thickness (symmetrical
synapses), and can be perforated or non-perforated. Synaptic ribbons Fig. 3.7 The arrangement of a complex synaptic unit. A cerebellar
synaptic glomerulus with excitatory (‘ +’) and inhibitory (‘ −’) synapses
grouped around a central axonal bouton. The directions of transmission
are shown by the arrows. +–+–
+–
+
Neuroglial cellAxon of Golgi cell Soma of granule cell
Mossy fibre
axon terminalDendrite ofGolgi cell
Fig. 3.8 Electron micrographs demonstrating
various types of synapse. A, A cross-section of a
dendrite (D) on which two synaptic boutons (B)
end. The upper bouton contains round vesicles,
and the lower bouton contains flattened vesicles
of the small type. A number of pre- and
postsynaptic (P) thickenings mark the specialized
zones of contact. B, A type I synapse
(S, postsynaptic site) containing both small, round, clear vesicles and also large, dense-cored vesicles
of the neurosecretory type. C, A large terminal
bouton (B) of an optic nerve afferent fibre, which is making contact with a number of postsynaptic
processes, in the dorsal lateral geniculate nucleus
of the rat. One of the postsynaptic processes (*)
also receives a synaptic contact from a bouton
(Bf) containing flattened vesicles. D, Reciprocal
synapses (S) between two neuronal processes in the olfactory bulb. (Courtesy of Professor AR
Lieberman, Department of Anatomy, University
College, London.)
**
A
BC
DPP
BB
B
Bf
S
SSDP
PP
BB
B
Bf
S
SSD | 92 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Neurones
47
CHAPTER 3
instances, types I and II synapses are found in close proximity, orien -
tated in opposite directions across the synaptic cleft (a reciprocal
synapse).
Mechanisms of synaptic activity
Synaptic activation begins with arrival of one or more action potentials
at the presynaptic bouton, which causes the opening of voltage-sensitive
calcium channels in the presynaptic membrane. The response time in
typical fast-acting synapses is then very rapid; classic neurotransmitter
(e.g. ACh, glutamate or GABA) is released in less than a millisecond.
Release-ready synaptic vesicles are docked to the presynaptic membrane
and primed through processes not yet fully understood. On Ca2+ influx
through voltage-sensitive channels, their membranes fuse to open a pore through which neurotransmitter diffuses into the synaptic cleft
(Eggermann et al 2012; Gray 1959).
Once the vesicle has discharged its contents, its membrane is incor -
porated into the presynaptic plasma membrane and is then recycled back into the bouton by endocytosis near the edges of the active zone.
The recycling time for a synaptic vesicle may be in the range of a few
seconds to minutes; newly recycled vesicles may be used instantly for
the next cycle of neurotransmitter release (cycling pool of vesicles). The
fusion of vesicles with the presynaptic membrane is responsible for the
observed quantal behaviour of neurotransmitter release, both during
neural activation and spontaneously, in the slightly leaky resting condi -
tion (Neher and Sakaba 2008; Suedhof 2012).
Postsynaptic events vary greatly, depending on the receptor mole -
cules and their related molecular complexes (Murakoshi and Yasuda 2012). Receptors are generally classed as either ionotropic or metabo-
tropic. Ionotropic receptors are multimeric protein complexes that
harbour intrinsic ion channels that can be operated by conformational
changes induced when neurotransmitter molecules bind the receptor
complex, causing a voltage change within the postsynaptic cell. Exam -
ples are the nicotinic ACh receptor and the related GABA
A receptor,
which are formed from five subunits, and the tetrameric ionotropic glutamate receptors, such as the N-methyl-D-aspartate (NMDA)
receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor. Alternatively, the receptor and ion channel may be
separate molecules, coupled by G-proteins, some via a complex cascade
of chemical interactions (a second messenger system), e.g. the adenylate
cyclase pathway. Postsynaptic effects are generally rapid and short-lived,
because the transmitter is quickly inactivated either by an extracellular
enzyme (e.g. acetylcholinesterase, AChE), or by uptake into neurones
or glial cells. Examples of such metabotropic receptors are the mus -
carinic ACh receptor and the dopamine receptor.
Neurohormones
Neurohormones are included in the class of molecules with neurotransmitter-like activity. They are synthesized in neurones and released into the blood circulation by exocytosis at synaptic bouton-like are found at sites of neurotransmission in the retina and inner ear. They
have a distinctive morphology, in that the synaptic vesicles are grouped
around a ribbon- or rod-like density orientated perpendicular to the
cell membrane (see Fig. 3.9).
Synaptic boutons make obvious close contacts with postsynaptic
structures but many other terminals lack specialized contact zones.
Areas of transmitter release occur in the varicosities of unmyelinated
axons, where effects are sometimes diffuse, e.g. the aminergic pathways
of the basal ganglia, and in autonomic fibres in the periphery. In some
instances, such axons may ramify widely throughout extensive areas of
the brain and affect the behaviour of very large populations of neu -
rones, e.g. the diffuse cholinergic innervation of the cerebral cortices. Pathological degeneration of these pathways can therefore cause wide -
spread disturbances in neural function.
Neurones express a variety of neurotransmitters, either as one class
of neurotransmitter per cell or more often as several. Good correlations exist between some types of transmitter and specialized structural
features of synapses. In general, asymmetric synapses with relatively small spherical vesicles are associated with acetylcholine (ACh), gluta -
mate, serotonin (5-hydroxytryptamine, 5-HT) and some amines; those with dense-core vesicles include many peptidergic synapses and
other amines (e.g. noradrenaline (norepinephrine), adrenaline (epine -
phrine), dopamine). Symmetrical synapses with flattened or pleomor-
phic vesicles have been shown to contain either GABA or glycine.
Neurosecretory endings found in various parts of the brain and in
neuroendocrine glands and cells of the dispersed neuroendocrine
system share many features with presynaptic boutons. They all contain
peptides or glycoproteins within dense-core vesicles. The latter are of
characteristic size and appearance: they are often ellipsoidal or irregular
in shape, and relatively large, e.g. oxytocin and vasopressin vesicles in
the neurohypophysis may be up to 200 nm in diameter.
Synapses may cause depolarization or hyperpolarization of the post -
synaptic membrane, depending on the neurotransmitter released and the classes of receptor molecule in the postsynaptic membrane. Depo-
larization of the postsynaptic membrane results in excitation of the
postsynaptic neurone, whereas hyperpolarization has the effect of tran -
siently inhibiting electrical activity. Subtle variations in these responses may also occur at synapses where mixtures of neuromediators are
present and their effects are integrated. For details of the synaptic organ -
ization of the brain, see Shepherd (2003).
Type I and II synapses
There are two broad categories of synapse, type I and type II. In active
zones of type I synapses the cytoplasmic density is thicker on the post-synaptic side. In type II synapses the pre- and postsynaptic densities are thinner and more symmetrical. Type I boutons contain a predominance
of small spherical vesicles approximately 50 nm in diameter, and type
II boutons contain oval or flattened vesicles. Throughout the CNS, type I synapses are generally excitatory and type II are inhibitory. In a few Fig. 3.9 The structural arrangements of different types of synaptic contact. Excitatory synapses Serial synapses Axosomatic
synapses
Bouton
de passageA
With small
clear spherical
vesiclesWith dense
catecholamine-
containing vesiclesExcitatory
to dendriteInhibitory
axo-axonal
synapse
With small
flattened
vesiclesWith large
flattened
vesiclesInhibitory to dendrite
Excitatory in opposite
direction
Neurosecretory
ending Reciprocal synapse Inhibitory synapsesDendriteCapillaryB
C Ribbon synapse
Retinal
rodAxo-initial segment
synapseNucleus | 93 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
48 SECTION 1
lie mainly in the brainstem, although their axons ramify widely into all
parts of the nervous system. Monoaminergic cells are also present in
the retina.
Noradrenaline is the chief transmitter present in sympathetic gangli -
onic neurones with endings in various tissues, notably smooth muscle
and glands, and in other sites including adipose and haemopoietic
tissues and the corneal epithelium. It is also found at widely distributed
synaptic endings within the CNS, many of them the terminals of neu -
ronal somata situated in the locus coeruleus in the medullary floor. The actions of noradrenaline depend on its site of action and vary with the
type of postsynaptic receptor, e.g. it strongly inhibits neurones of
the submucosal plexus of the intestine and of the locus coeruleus via α
2-adrenergic receptors, whereas it mediates depolarization, producing
vasoconstriction, via β-receptors in vascular smooth muscle. Adrenaline
is present in central and peripheral nervous pathways and occurs
with noradrenaline in the suprarenal medulla. Both adrenaline and noradrenaline are found in dense-cored synaptic vesicles approximately
50 nm in diameter.
Dopamine is a neuromediator of considerable clinical importance,
found mainly in neurones with cell bodies in the telencephalon,
diencephalon and mesencephalon. A major dopaminergic neuronal
population in the midbrain constitutes the substantia nigra, so called
because its cells contain neuromelanin, a black granular by-product
of dopamine synthesis. Dopaminergic endings are particularly numer-ous in the corpus striatum, limbic system and cerebral cortex. Structur -
ally, dopaminergic synapses contain numerous dense-cored vesicles that resemble those containing noradrenaline. Pathological reduction
in dopaminergic activity has widespread effects on motor control,
affective behaviour and other neural activities, as seen in Parkinson’s syndrome.
Serotonin and histamine are found in neurones mainly within the
CNS. Serotonin is typically synthesized in small midline neuronal clus -
ters in the brainstem, mainly in the raphe nuclei; the axons from these neurones ramify extensively throughout the entire brain and spinal
cord. Synaptic terminals contain rounded, clear vesicles approximately
50 nm in diameter and are of the asymmetrical type. Histaminergic
neurones appear to be relatively sparse and are restricted largely to the
hypothalamus.
Amino acids
There are three major amino acids: GABA, glutamate and glycine, which bind to specific receptors (Barrera and Edwardson 2008). GABA is a
major inhibitory transmitter released at the terminals of local circuit
neurones within the brainstem and spinal cord (e.g. the recurrent inhib -
itory Renshaw loop), cerebellum (where it is the main transmitter of Purkinje cells), basal ganglia, cerebral cortex, thalamus and subthala-
mus. It is stored in flattened or pleomorphic vesicles within symmetrical
synapses. GABA may be inhibitory to postsynaptic neurones, or may
mediate either presynaptic inhibition or facilitation, depending on the
synaptic arrangement (Gassmann and Bettler 2012).
Glutamate is the major excitatory transmitter present widely within
the CNS, including the major projection pathways from the cortex to
the thalamus, tectum, substantia nigra and pontine nuclei. It is found
in the central terminals of the auditory and trigeminal nerves, and in
the terminals of parallel fibres ending on Purkinje cells in the cerebel -
lum. Structurally, glutamate is associated with asymmetrical synapses
containing small (approximately 30 nm), round, clear synaptic vesicles
(Contractor et al 201 1). For further reading, see Willard and Koochek -
pour (2013).
Glycine is a well-established inhibitory transmitter of the CNS, par -
ticularly the lower brainstem and spinal cord, where it is mainly found in local circuit neurones. Recent evidence suggests that glycine may also
be released from glutamatergic axon terminals to participate in activa -
tion of NMDA receptors, and from astrocytes into the synaptic cleft via activation of non-NMDA-type glutamatergic ionotropic receptors in
the glial cell membrane (see Harsing and Matyus (2013) for further
references).
ATP and adenosine
ATP serves not only as a universal energy substrate, but also as an extra -
cellular signalling molecule. Specific ionotropic (P2X) and metabo-
tropic (P2Y) receptors are expressed in neurones and even more
prominently on all types of glial cell. Adenosine is a degradation product of ATP and has specific metabotropic receptors that may be
located presynaptically (Burnstock et al 201 1).
Nitric oxide
Nitric oxide (NO) is of considerable importance at autonomic and enteric synapses, where it mediates smooth muscle relaxation. It structures. As with classic endocrine gland hormones, they may act at
great distances from their site of secretion. Neurones secrete into the
CSF or local interstitial fluid to affect other cells, either diffusely or at
a distance. To encompass this wide range of phenomena the general
term neuromediation has been used, and the chemicals involved are
called neuromediators.
Neuromodulators
Some neuromediators do not appear to affect the postsynaptic mem -
brane directly but they can affect its responses to other neuromediators,
either enhancing their activity (by increasing or prolonging the immedi -
ate response), or perhaps limiting or inhibiting their action. These substances are called neuromodulators. A single synaptic terminal may
contain one or more neuromodulators in addition to a neurotransmit -
ter, usually (though not always) in separate vesicles. Neuropeptides (see below) are nearly all neuromodulators, at least in some of their actions.
They are stored within dense granular synaptic vesicles of various sizes
and appearances.
Development and plasticity of synapses
Embryonic synapses first appear as inconspicuous dense zones flanking synaptic clefts. Immature synapses often appear after birth, suggesting
that they may be labile, and are reinforced if transmission is function-
ally effective, or withdrawn if redundant. This is implicit in some theo -
ries of memory (Squire and Kandel 2008), which postulate that synapses are modifiable by frequency of use, to establish preferential conduction
pathways. Evidence from hippocampal neurones suggests that even
brief synaptic activity can increase the strength and sensitivity of the
synapse for some hours or longer (long-term potentiation, LTP). During
early postnatal life, the normal developmental increase in numbers and
sizes of synapses and dendritic spines depends on the degree of neural
activity and is impaired in areas of damage or functional deprivation.
Neurotransmitter molecules
Until recently, the molecules known to be involved in chemical syn -
apses were limited to a fairly small group of classic neurotransmitters,
e.g. ACh, noradrenaline (norepinephrine), adrenaline (epinephrine),
dopamine and histamine, all of which had well-defined rapid effects
on other neurones, muscle cells or glands. However, many synaptic
interactions cannot be explained on the basis of classic neurotransmit -
ters, and it is now known that other substances, particularly some amino acids such as glutamate, glycine, aspartate, GABA and the
monoamine, serotonin, also function as transmitters. Substances first
identified as hypophysial hormones or as part of the dispersed neuroen -
docrine system (see below) of the alimentary tract, can be detected widely throughout the CNS and PNS, often associated with functionally
integrated systems. Many of these are peptides; more than one hundred
(together with other candidates) function mainly as neuromodulators
and influence the activities of classic transmitters.
Acetylcholine
Acetylcholine (ACh) is perhaps the most extensively studied neuro -
transmitter of the classic type. Its precursor, choline, is synthesized in the neuronal soma and transported to the axon terminals, where it is
acetylated by the enzyme choline acetyl transferase (ChAT), and stored
in clear spherical vesicles 40–50 nm in diameter. ACh is synthesized by
motor neurones and released at all their motor terminals on skeletal muscle. It is released by preganglionic fibres at synapses in parasympa -
thetic and sympathetic ganglia, and many parasympathetic, and some sympathetic, ganglionic neurones are cholinergic. ACh is also associ -
ated with the degradative extracellular enzyme AChE, which inactivates the transmitter by converting it to choline.
The effects of ACh on nicotinic receptors (i.e. those in which nicotine
is an agonist) are rapid and excitatory. In the CNS, the nicotinic ACh
receptor mediates the effect of tobacco (for review, see Albuquerque
et al (2009)). In the peripheral autonomic nervous system, the slower,
more sustained excitatory effects of cholinergic autonomic endings are
mediated by muscarinic receptors via a second messenger system.
Monoamines
Monoamines include the catecholamines (noradrenaline (norepine -
phrine), adrenaline (epinephrine) and dopamine), the indoleamine
serotonin (5-hydroxytryptamine, 5-HT) and histamine (Haas et al
2008). They are synthesized by neurones in sympathetic ganglia and by
their homologues, the chromaffin cells of the suprarenal medulla and paraganglia. Within the CNS, the somata of monoaminergic neurones | 94 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Central glia
49
CHAPTER 3
ASTROCYTES
Astrocytes are the most abundant and diverse glial cell type but their
identity is not well defined (Matyash and Kettenmann 2010). There is
no common marker that labels all astrocytes, in the way that myelin
basic protein is a marker for oligodendrocytes or the calcium-binding
protein Iba1 is a marker for microglia. A commonly used marker is the
expression of glial fibrillary acidic protein (GFAP), which forms inter -
mediate filaments, but GFAP is not expressed in all astrocytes.
The morphology of astrocytes is extremely diverse. Classically, two
forms were distinguished: protoplasmic and fibrous astrocytes. Proto -
plasmic astrocytes (star-shaped cells) are found in grey matter, possess
several stem processes that branch further into a very complex network,
and contact synapses, both at the pre- and postsynaptic membranes.
Fibrous astrocytes are predominantly found in white matter and their
processes are often orientated in parallel with the axons. Radial glial
cells are found early in development and serve as stem cells for neu -
rones and glial cells. They may be categorized as astrocytes because they transform later in development into typical astrocytes. There are a
number of other types of astrocyte with specialized morphologies. Berg -
mann glial cells in the cerebellum have somata in the Purkinje cell layer, processes that intermingle with the dendritic trees of the Purkinje
neurones and terminal end-feet at the pial surface. Müller cells in the retina have a radial morphology and span the entire retina. Other
astrocytic cells are tanycytes, velate astrocytes (cerebellum) and pitui -
cytes (infundibulum and neurohypophysis of the pituitary gland). Pituicyte processes end mostly on endothelial cells in the neurohypo -
physis and tuber cinereum.
Astrocyte complexity and morphological diversity has reached the
highest evolutionary level in humans ( Fig. 3.1 1). A single astrocyte may
enwrap several neuronal somata and make contacts with tens of thou -
sands of individual synapses; bipolar astrocytes located in layer 5 and
6 of the cortex may extend processes up to 1 mm long.
Astrocytes in grey matter form a syncytium in which cells are inter -
connected by gap junctions, permitting the exchange of ions (e.g. calcium, propagated in waves) and small molecules such as ATP or
glucose. They are the only cells in the brain capable of converting
glucose into glycogen, which serves as an energy store. Before re-releasing
glucose, astrocytes convert it to lactate, which is taken up by neurones;
failure in glucose flow through the astrocytic network results in impair -
ment of neuronal function.
Astrocytes not only respond to neuronal activity but also modulate
that activity. They enwrap all penetrating and intracerebral arterioles and capillaries, control the ionic and metabolic environment of the
neuropil and mediate neurovascular coupling. They form specialized
structures that contact either the pial surface (as the glia limitans) or
blood vessels; their end-feet entirely enwrap blood vessels and are
instrumental in the induction of the blood–brain barrier.
Traumatic injury to the CNS induces astrogliosis, seen as a local
increase in the number and size of GFAP-positive cells and a character -
istic extensive meshwork of processes. The microenvironment of this glial scar, which may also include cells of oligodendrocyte lineage and myelin debris, plays an important role in inhibiting regrowth of
damaged CNS axons (Robel et al 201 1, Seifert et al 2006).
functions in several types of synaptic plasticity, including hippocampal
long-term potentiation (LTP), when it may act as a retrograde messen -
ger after postsynaptic NMDA receptor activation. NO is able to diffuse freely through cell membranes, and so is not under such tight quantal
control as vesicle-mediated neurotransmission.
Neuropeptides
Many neuropeptides coexist with other neuromediators in the same
synaptic terminals. As many as three peptides often share a particular
ending with a well-established neurotransmitter, in some cases within
the same synaptic vesicles. Some peptides occur in both the CNS and
the PNS, particularly in the ganglion cells and peripheral terminals
of the ANS, whilst others are entirely restricted to the CNS. Only a
few examples are given here.
Most of the neuropeptides are classified according to the site where
they were first discovered. For example, the gastrointestinal peptides
were initially found in the gut wall, and a group that includes releasing
hormones, adenohypophysial and neurohypophysial hormones was
first associated with the pituitary gland. Some of these peptides are
closely related to each other in their chemistry because they are derived
from the same gene products (e.g. the pro-opiomelanocortin group),
which are cleaved to produce smaller peptides.
Substance P (SP) was the first of the peptides to be characterized as
a gastrointestinal neuromediator and is considered to be the proto -
typic neuropeptide. It is an 1 1-amino-acid polypeptide that belongs to the tachykinin neuropeptide family, and is a major neuromediator in
the brain and spinal cord. Contained within large granular synaptic
vesicles, SP is found in approximately 20% of dorsal root and trigemi -
nal ganglion cells, in particular in small nociceptive neurones, and in some fibres of the facial, glossopharyngeal and vagal nerves. Within
the CNS, SP is present in several apparently unrelated major pathways,
and has been described in the limbic system, basal ganglia, amygdala
and hypothalamus. Its known action is prolonged postsynaptic
excitation, particularly from nociceptive afferent terminals, which sus -
tains the effects of noxious stimuli. SP is one of the main neuropep -
tides that trigger an inflammatory response in the skin and has
also been implicated in the vomiting reflex, changes in cardiovascular
tone, stimulation of salivary secretion, smooth muscle contraction,
and vasodilation.
Vasoactive intestinal polypeptide (VIP), another gastrointestinal
peptide, is widely present in the CNS, where it is probably an excitatory
neurotransmitter or neuromodulator. It is found in distinctive bipolar
neurones of the cerebral cortex; small dorsal root ganglion cells, par -
ticularly of the sacral region; the median eminence of the hypothala -
mus, where it may be involved in endocrine regulation; intramural
ganglion cells of the gut wall; and sympathetic ganglia.
Somatostatin (ST, somatotropin release inhibiting factor) has a
broad distribution within the CNS, and may be a central neurotransmit -
ter or neuromodulator. It also occurs in small dorsal root ganglion cells. Beta-endorphin, leu- and metenkephalins, and the dynorphins belong
to a group of peptides called the naturally occurring opiates that possess
analgesic properties. They bind to opiate receptors in the brain where,
in general, their action seems to be inhibitory. Enkephalins have been
localized in many areas of the brain. Their particular localization in the
septal nuclei, amygdaloid complex, basal ganglia and hypothalamus
suggests that they are important mediators in the limbic system and in
the control of endocrine function. They have also been implicated
strongly in the central control of pain pathways, because they are found
in the peri-aqueductal grey matter of the midbrain, a number of reticu -
lar raphe nuclei, the spinal nucleus of the trigeminal nerve and the substantia gelatinosa of the spinal cord. The enkephalinergic pathways
exert an important presynaptic inhibitory action on nociceptive affer -
ents in the spinal cord and brainstem. Like many other neuromediators, enkephalins also occur widely in other parts of the brain in lower
concentrations.
CENTRAL GLIA
Glial (neuroglial) cells (Fig 3.10) vary considerably in type and number
in different regions of the CNS. There are two major groups, macroglia
(astrocytes and oligodendrocytes) and microglia, classified according to origin. Macroglia arise within the neural plate, in parallel with neu -
rones, and constitute the great majority of glial cells. Their functions are diverse and are now known to extend beyond a passive supporting role (reviewed in Kettenmann and Ransom (2012)). Microglia have a
small soma (see Fig. 3.19) and are derived from a distinct lineage of
monocytic cells originating from the yolk sac.Fig. 3.10 The different types of non-neuronal cell in the CNS and their
structural organization and interrelationships with each other and with
neurones. Pia materSubpial end-foot
Oligodendrocyte Capillary Myelinated
axonAstrocyteAstrocytePerineuronal
end-foot
Pericapillary
end-footMicroglial cellTanycyte
Ependymal cell VentricleNeurone | 95 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Nervous system
49.e1
CHAPTER 3
Astrocytes control the diameter of the vessels they contact and can
trigger either their dilation or their contraction, depending on the sub -
stances they release and the levels of associated neuronal activity. They
express water channels (aquaporins) at the end-feet covering the capil -
laries; it has been suggested that this may represent the means by which
astrocytes control brain volume (Tait et al 2008), and it may be relevant
to understanding mechanisms of brain tissue swelling, a major clinical complication. Astrocytes express different glutamate transporters that
efficiently maintain low levels of extracellular glutamate, which is
excitotoxic. Internalized glutamate is converted into glutamine and released from astrocytes to be taken up by local neurones and recon -
verted to glutamate via the glutamate–glutamine cycle. They play a similar role in controlling extracellular GABA levels via expression of
GABA transporters. Astrocytes possess both passive and active mecha -
nisms to control extracellular potassium levels at a resting level of about
3 mmol. They also express transporters that regulate pH and are thought
to play an important role in controlling extracellular pH in the brain. For further reading on the concept of the ‘tripartite synapse’, where
astrocytic processes interact with pre- and postsynaptic neuronal ele -
ments, see Haydon and Carmignoto (2006).
It has become evident that astrocytes are involved in the modulation
of long-term potentiation (considered as a cellular mechanism of memory formation) and heterosynaptic depression. They modulate
neuronal activity by releasing neuroactive substances such as
D-serine,
ATP or glutamate; it is unclear whether they express all the elements
required for neurotransmitter release by a vesicular mechanism (Parpura
and Zorec 2010). | 96 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
50 SECTION 1
which means that a free exchange of molecules occurs between blood
and adjacent brain. Most of these areas are situated close to the ventri -
cles and are known as circumventricular organs; these areas make up less than 1% of the total area of the brain. Elsewhere, unrestricted
diffusion through the blood–brain barrier is only possible for sub-stances that can cross biological membranes because of their lipophilic
character. Lipophilic molecules may be actively re-exported by the
brain endothelium.
Breakdown of the blood–brain barrier occurs when the brain is
damaged by ischaemia or infection, and is also associated with primary
and metastatic cerebral tumours. Reduced blood flow to a region of the
brain alters the permeability and regulatory transport functions of the
barrier locally; the increased stress on compromised endothelial cells
results in leakage of fluid, ions, serum proteins and intracellular sub -
stances into the extracellular space of the brain. The integrity of the barrier can be evaluated clinically using computed tomography and
functional magnetic resonance imaging. Breakdown of the blood–brain
barrier may be seen at postmortem in jaundiced patients who have had
an infarction. Normally, the brain, spinal cord and peripheral nerves
remain unstained by the bile post mortem, although the choroid plexus
is often stained a deep yellow. However, areas of recent infarction (1–3
days) will also be stained by bile pigment because of the localized
breakdown of the blood–brain barrier.
OLIGODENDROCYTES
Oligodendrocytes myelinate CNS axons and are most commonly seen
as intrafascicular cells in myelinated tracts ( Figs 3.13–3.14). They
usually have round nuclei and their cytoplasm contains numerous mitochondria, microtubules and glycogen. They display a spectrum of
morphological variation, from cells with large euchromatic nuclei and
pale cytoplasm, to cells with heterochromatic nuclei and dense cyto -
plasm. In contrast to Schwann cells, which myelinate only one axonal segment, individual oligodendrocytes myelinate up to 50 axonal seg -
ments. Some oligodendrocytes are not associated with axons, and are either precursor cells or perineuronal (satellite) oligodendrocytes with
processes that ramify around neuronal somata.
Within tracts, interfascicular oligodendrocytes are arranged in long
rows interspersed at regular intervals with single astrocytes. Since oli -
godendrocyte processes are radially aligned to the axis of each row, myelinated tracts typically consist of cables of axons myelinated by a
row of oligodendrocytes running down the axis of each cable.
Oligodendrocytes originate from the ventricular neurectoderm and
the subependymal layer in the fetus, and continue to be generated from
the subependymal plate postnatally. Stem cells migrate and seed into
white and grey matter to form a pool of adult progenitor cells, which
can later differentiate to replenish defunct oligodendrocytes, and pos -
sibly remyelinate axons in pathologically demyelinated regions. These
cells display a highly branching morphology and express a specific
chondroitin sulphate proteoglycan (Neuron Glia 2 (NG2) in rats and
its homologue, melanoma cell surface chondroitin sulphate proteo -
glycan (MSCP), in humans). The name NG2 cell is used to describe the cells in both species: several different names have also been used since
it was first recognized, including polydendrocyte (Nishiyama et al
2009) and syantocyte (Butt et al 2005). NG2 cells express a complex
set of voltage-gated channels and ionotropic receptors for glutamate Blood–brain barrier
Proteins circulating in the blood enter most tissues of the body except
those of the brain, spinal cord and peripheral nerves. This concept of a
blood–brain or a blood–nerve barrier applies to many substances –
some are actively transported across the blood–brain barrier, others are
actively excluded. The blood–brain barrier is located at the capillary
endothelium within the brain and is dependent on the presence of tight
junctions (occluding junctions, zonulae adherentes) between endothe -
lial cells coupled with a relative lack of transcytotic vesicular transport.
The tightness of the barrier is substantially supported by the close apposition of astrocytes, which direct the formation of endothelial tight
junctions, to blood capillaries (reviewed in Abbott et al (2006), Cardoso
et al (2010); Fig. 3.12).
The blood–brain barrier develops during embryonic life but may
not be fully completed by birth. There are certain areas of the adult brain where the endothelial cells are not linked by tight junctions, Fig. 3.11 Human protoplasmic astrocytes are
larger and more complicated than their rodent
counterparts. A, A typical mouse protoplasmic
astrocyte. Glial fibrillary acidic protein (GFAP)
immunostain; white. SB = 20 µm. B, A typical
human protoplasmic astrocyte to the same scale.
SB = 20 µm. (From Oberheim NA, Takano T, Han
X, et al 2009 Uniquely hominid features of adult
human astrocytes. J Neurosci 29:3276–87.)
A B
Fig. 3.12 The relationship between the glia limitans, perivascular cells
and blood vessels within the brain, in longitudinal ( A) and transverse
(B) sections. A sheath of astrocytic end-feet wraps around the vessel and,
in vessels larger than capillaries, its investment of pial meninges. Vascular
endothelial cells are joined by tight junctions and supported by pericytes;
perivascular macrophages lie outside the endothelial basal lamina (light
blue). Astrocyte end-foot
Basal lamina
Pia mater
(larger vessels only)
Pericyte under
the basal lamina
Perivascular cell
(macrophage)
Endothelium
Basal laminaPericyte Astrocyte
end-footA
B | 97 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Central glia
51
CHAPTER 3
and GABA; they form direct synapses with axons, enabling transient
activation of these receptors (Hill and Nishiyama 2014). There is con -
siderable support for the view that the NG2 cell is a distinct glial type.
Nodes of Ranvier and incisures of
Schmidt–Lanterman
The territory ensheathed by an oligodendrocyte (or Schwann cell)
process defines an internode, the interval between internodes is called a node of Ranvier (Fig. 3.15) and the territory immediately adjacent to
the nodal gap is a paranode, where loops of oligodendrocyte cytoplasm
abut the axolemma. Nodal axolemma is contacted by fine filopodia of
perinodal cells, which have been shown in animal studies to have a
presumptive adult oligodendrocyte progenitor phenotype; their func -
tion is unknown. Schmidt–Lanterman incisures are helical decompac -
tions of internodal myelin where the major dense line of the myelin
sheath splits to enclose a spiral of oligodendrocyte cytoplasm. Their
structure suggests that they may play a role in the transport of molecules
across the myelin sheath, but their function is not known.
MYELIN AND MYELINATION
Myelin is formed by oligodendrocytes (CNS) and Schwann cells (PNS). A single oligodendrocyte may ensheathe up to 50 separate axon seg -
ments, depending on calibre, whereas myelinating Schwann cells
ensheathe axons on a 1 : 1 basis.
In general, myelin is laid down around axons above 2 µm in diam -
eter. However, the critical minimal axon diameter for myelination is
smaller and more variable in the CNS than in the PNS (approximately
0.2 µm in the CNS compared with 1–2 µm in the PNS). There is con -
siderable overlap between the size of the smallest myelinated and the largest unmyelinated axons, and so axonal calibre is unlikely to be the
only factor in determining myelination. Moreover, the first axons to
become ensheathed ultimately attain larger diameters than those that
are ensheathed at a later date. There is a reasonable linear relationship
between axon diameter and internodal length and myelin sheath thick -
ness: as the sheath thickens from a few lamellae to up to 200, the axon
may also grow from 1 to 15 µm in diameter. Internodal lengths increase
about 10-fold during the same time (Nave 2010).
It is not known precisely how myelin is formed in either PNS or
CNS. Akt/mTOR (mammalian (or mechanistic) target of rapamycin) signalling has emerged as one of the major pathways involved in myeli -
nation; it has been implicated in the regulation of several steps during the development of myelinating Schwann cells and oligodendrocytes
(Norrmén and Suter 2013). In the CNS, myelination also depends in
part on expression of a protein (Wiskott–Aldrich syndrome protein
family verprolin homologous; WAVE), which influences the actin
cytoskeleton, oligodendrocyte lamellipodia formation and myelination
(Kim et al 2006). The ultrastructural appearance of myelin is usually
explained in terms of the spiral wrapping of an extensive, flat glial
process (lamellipodium) around an axon, and the subsequent extrusion
of cytoplasm from the sheath at all points other than incisures and
paranodes. In this way, the compacted external surfaces of the plasma
membrane of the ensheathing glial cell are thought to produce the minor dense lines, and the compacted inner cytoplasmic surfaces, the major dense lines, of the mature myelin sheath (Fig. 3.16). These lines, first described in early electron microscope studies of the myelin sheath, correspond to the intraperiod and period lines respectively, defined in X-ray studies of myelin. The inner and outer zones of occlusion of the spiral process are continuous with the minor dense line and are called Fig. 3.13 The ensheathment of a number of axons by the processes of
an oligodendrocyte. The oligodendrocyte soma is shown in the centre
and its myelin sheaths are unfolded to varying degrees to show their
extensive surface area. (Modified from Morell P, Norton WT (1980, May).
Myelin, Scientific American, 242(5), 88–90, 92, 96 and Raine CS (1984),
Morphology of Myelin and Myelination. In Myelin, 2nd ed. P Morell (ed)
New York (Plenum Press), by permission.)Node of Ranvier NucleusOligodendrocyte
Outer loopLateral loop
Axon Longitudinal
incisuresInner loop Myelin sheath
Fig. 3.14 A, An oligodendrocyte enwrapping several axons with myelin,
demonstrated in a whole-mounted rat anterior medullary velum,
immunolabelled with antibody to an oligodendrocyte membrane antigen.
B, A confocal micrograph of a mature myelin-forming oligodendrocyte in
an adult rat optic nerve, iontophoretically filled with an immunofluorescent
dye by intracellular microinjection. (A, Courtesy of Fiona Ruge.
B, Prepared by Professor A Butt, Portsmouth, and Kate Colquhoun, formerly Division of Physiology, GKT School of Medicine, London.)
A
BFig. 3.15 A node of Ranvier (N) in the central nervous system of a rat.
The pale-staining axon (A) is ensheathed by oligodendrocyte myelin
(arrow), apart from a short, exposed region at the node. Toluidine blue
stained resin section. (Courtesy of Dr Clare Farmer, King’s College,
London.)
A
N | 98 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
52 SECTION 1
ependymal lining of the ventricles but four major types have been
described. These are: general ependymal, which overlies grey matter;
general ependymal, which overlies white matter; specialized areas of
ependyma in the third and fourth ventricles; and choroidal epithelium.
The ependymal cells overlying areas of grey matter are cuboidal.
Each cell bears approximately 20 central apical cilia, surrounded by
short microvilli. The cells are joined by gap junctions and desmosomes.
Beneath them there may be a subependymal (or subventricular) zone,
from two to three cells deep, consisting of cells that generally resemble
ependymal cells. In rodents, the subventricular zone contains neural
progenitor cells, which can give rise to new neurones, but the existence
of these stem cells in the adult human brain is controversial (Sanai et al
201 1, Kempermann 201 1). The capillaries beneath the ependymal cells
have no fenestrations and few transcytotic vesicles, which is typical of the CNS. Where the ependyma overlies myelinated tracts of white
matter, the cells are much flatter and few are ciliated. There are gap
junctions and desmosomes between these cells, but their lateral margins
interdigitate, unlike their counterparts overlying grey matter. No sub -
ependymal zone is present.
Specialized areas of ependymal cells called the circumventricular
organs are found in four areas around the margins of the third ventricle: namely, the lining of the median eminence of the hypothalamus; the
subcommissural organ; the subfornical organ; and the vascular organ
of the lamina terminalis. The area postrema, at the inferoposterior limit
of the fourth ventricle, has a similar structure. In all of these sites the
ependymal cells are only rarely ciliated and their ventricular surfaces
bear many microvilli and apical blebs. They have numerous mitochon -
dria, well-formed Golgi complexes and rather flattened basal nuclei. They are joined laterally by tight junctions, which form a barrier to the
passage of materials across the ependyma, and by desmosomes. Many
of the cells are tanycytes (ependymal astrocytes) and have basal
processes that project into the perivascular space surrounding the
underlying capillaries. Significantly, these capillaries are fenestrated and therefore do not form a blood–brain barrier. It is believed that neu -
ropeptides can pass from nervous tissue into the CSF by active transport through the ependymal cells in these specialized areas, and so access a wide population of neurones via the permeable ependymal lining of the rest of the ventricle.
The ependyma is highly modified where it lies adjacent to the vas -
cular layer of the choroid plexuses.the inner and outer mesaxons. For further reading on aspects of myeli -
nation, see Bakhti et al (2013).
There are significant differences between central and peripheral
myelin, reflecting the fact that oligodendrocytes and Schwann cells
express different proteins during myelinogenesis. The basic dimensions
of the myelin membrane are different. CNS myelin has a period repeat
thickness of 15.7 nm whereas PNS myelin has a period to period line
thickness of 18.5 nm, and the major dense line space is approximately
1.7 nm in CNS myelin, compared with 2.5 nm in PNS myelin. Myelin
membrane contains protein, lipid and water, which forms at least 20%
of the wet weight. It is a relatively lipid-rich membrane and contains
70–80% lipid. All classes of lipid have been found; perhaps not surpris -
ingly, the precise lipid composition of PNS and CNS myelin is different. The major lipid species are cholesterol (the most common single mol -
ecule), phospholipids and glycosphingolipids. Minor lipid species include galactosylglycerides, phosphoinositides and gangliosides. The
major glycolipids are galactocerebroside and its sulphate ester, sul -
phatide; these lipids are not unique to myelin but they are present
in characteristically high concentrations. CNS and PNS myelin also
contain low concentrations of acidic glycolipids, which constitute
important antigens in some inflammatory demyelinating states. Gan -
gliosides, which are glycosphingolipids characterized by the presence of sialic acid (N-acetylneuraminic acid), account for less than 1% of the
lipid in myelin.
A relatively small number of protein species account for the majority
of myelin protein. Some of these proteins are common to both PNS
and CNS myelin, but others are different. Proteolipid protein (PLP)
and its splice variant DM20 are found only in CNS myelin, whereas myelin basic protein (MBP) and myelin associated glycoprotein (MAG)
occur in both. MAG is a member of the immunoglobulin supergene
family, and is localized specifically at those regions of the myelin
segment where compaction starts: namely, the mesaxons and inner
periaxonal membranes, paranodal loops and incisures, in both CNS
and PNS sheaths. It is thought to have a functional role in membrane
adhesion.
In the developing CNS, axonal outgrowth precedes the migration of
oligodendrocyte precursors, and oligodendrocytes associate with and
myelinate axons after their phase of elongation; oligodendrocyte myelin
gene expression is not dependent on axon association. In marked con -
trast, Schwann cells in the developing PNS are associated with axons during the entire phase of axonal growth. Myelination does not occur
simultaneously in all parts of the body in late fetal and early postnatal
development. White matter tracts and nerves in the periphery have their
own specific temporal patterns that relate to their degree of functional
maturity.
Mutations of the major myelin structural proteins have now been
recognized in a number of inherited human neurological diseases. As
would be expected, these mutations produce defects in myelination and
in the stability of nodal and paranodal architecture that are consistent
with the suggested functional roles of the relevant proteins in maintain -
ing the integrity of the myelin sheath.
EPENDYMA
Ependymal cells line the ventricles ( Fig. 3.17; see Fig. 3.10) and central
canal of the spinal cord. They form a single-layered epithelium that
varies from squamous to columnar in form. At the ventricular surface, cells are joined by gap junctions and occasional desmosomes. Their apical surfaces have numerous microvilli and/or cilia, the latter contrib -
uting to the flow of CSF. There is considerable regional variation in the Fig. 3.16 Suggested stages in
myelination of a peripheral axon by an
ensheathing Schwann cell.
AxonInner
mesaxonOuter
mesaxonSchwann cell
cytoplasmBasal
lamina
Fig. 3.17 Ciliated columnar epithelial lining of the lateral ventricle (V),
overlying the subventricular zone (SVZ). C, cilia; E, ependymal cells. Mouse tissue, toluidine blue stained resin section.
V
C
E
SVZ | 99 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Central glia
53
CHAPTER 3
MICROGLIA
Microglia are the endogenous immune cells of the brain (Kettenmann
et al 201 1, Eggen et al 2013). They originate from an embryonic mono -
cyte precursor and invade the brain early during development. While
the invading cells have an ameboid morphology, microglial cells in a
mature brain are highly ramified cells. They have elongated nuclei, scant
cytoplasm and several highly branched processes. They occupy a defined
territory in the brain parenchyma and are found in all areas of the CNS
including optic nerve, retina and spinal cord. Their density shows little
variation.
Resting microglia, a term used to refer to microglia in the normal
brain, should more accurately be described as surveying microglia.
Microglial processes are fast-moving structures that rapidly scan their
territory while the soma remains fixed in position. Microglial cells
express receptors for neurotransmitters and thus can sense neuronal
activity. It is likely that they interact with synapses, from which it has
been inferred that they may influence synaptic transmission.
All pathological changes in the brain result in the activation of
microglial cells (Fig. 3.19), e.g. activated microglia are found in the
brain tissue of multiple sclerosis, Alzheimer’s disease and stroke
patients. The most common indication of their activation is a change
from a ramified to an ameboid morphology, which may occur within
a few hours of the onset of injury or disease process.
In general, microglia respond to two types of signal: ‘on’ signals, which
either appear de novo or are strongly upregulated, e.g. cell wall compo -
nents of invading bacteria; and ‘off’ signals, which are normally present but disappear or decrease in pathological states, e.g. defined cytokines
or neurotransmitters. Both types of event are interpreted as signals for activation. The functional repertoire of activated microglia includes pro -
liferation; migration to the site of injury; expression of major histocom -
patibility complex (MHC) II molecules to interact with infiltrating
lymphocytes; and the release of a variety of different substances including
chemokines, cytokines and growth factors. These cells are therefore capa -
ble of significantly influencing ongoing pathological processes.
Microglial cells are the professional phagocytes of the nervous
system and actively migrate through tissue. A number of factors such as ATP and complement factors act as chemoattractants. This behaviour is
relevant not only in pathology but also during development where
microglial cells remove apoptotic cells. After a pathological insult,
microglial cells revert to their surveying phenotype, re-acquiring a rami -
fied morphology.
Entry of inflammatory cells into the brain
Although the CNS has long been considered to be an immunologically privileged site, lymphocyte and macrophage surveillance of the brain
may be a normal, but very low-grade, activity that is enhanced in
disease. Lymphocytes can enter the brain in response to virus infections
and as part of the autoimmune response in multiple sclerosis. Activated,
but not resting, lymphocytes pass through the endothelium of small
venules, a process that requires the expression of recognition and adhe -
sion molecules (induced following cytokine activation), and subse-quently migrate into the brain parenchyma. Within the CNS, microglia
can be induced by T-cell cytokines to act as efficient antigen-presenting
cells. After leaving the CNS, lymphocytes probably drain along lym -
phatic pathways to regional cervical lymph nodes.Choroid plexus
The choroid plexus forms the CSF and actively regulates the concentra -
tion of molecules in the CSF. It consists of highly vascularized masses of pia mater enclosed by pockets of ependymal cells. The ependymal
cells resemble those of the circumventricular organs, except that they
do not have basal processes, but form a cuboidal epithelium that rests
on a basal lamina adjacent to the enclosed fold of meningeal pia mater
and its capillaries (Fig. 3.18). The cells have numerous long microvilli
with only a few cilia interspersed between them. They also have many
mitochondria, large Golgi complexes and basal nuclei, features consist -
ent with their secretory activity; they produce most components of the CSF. They are linked by tight junctions forming a transepithelial barrier
(a component of the blood–CSF barrier), and by desmosomes. Their
lateral margins are highly folded.
The choroid plexus has a villous structure where the stroma is com-
posed of pial meningeal cells, and contains fine bundles of collagen
and blood vessels. Choroidal capillaries are lined by a fenestrated
endothelium. During fetal life, erythropoiesis occurs in the stroma,
which is occupied by bone marrow-like cells. In adult life, the stroma
contains phagocytic cells, which, together with the cells of the choroid
plexus epithelium, phagocytose particles and proteins from the ven -
tricular lumen.
Age-related changes occur in the choroid plexus, which can be
detected by neuroimaging. Calcification of the choroid plexus can be detected by X-ray or CT scan very rarely in individuals in the first decade
of life and in the majority in the eighth decade. The incidence of calci -
fication rises sharply, from 35% of CT scans in the fifth decade to 75% in the sixth decade. Visible calcification is usually restricted to the
glomus region of the choroid plexus, i.e. the vascular bulge in the
choroid plexus as it curves to follow the anterior wall of the lateral
ventricle into the temporal horn.
Fig. 3.18 A, A choroid plexus within the lateral ventricle. Frond-like
projections of vascular stroma derived from the pial meninges are
covered with a low columnar epithelium that secretes cerebrospinal fluid. Mouse tissue, toluidine blue stained resin section. B, The arrangement of
tissues forming the choroid plexus. Arachnoid
materPia mater
CNSSubarachnoid
spaceChoroid
fissureCapillary
CNS
VentricleChoroid epithelium Choroid capillary Ependyma
A
B
Fig. 3.19 Activated microglial cells in the human central nervous system,
in a biopsy from a patient with Rasmussen’s encephalitis, visualized using MHC class II antigen immunohistochemistry. (Courtesy of Dr Norman Gregson, Division of Neurology, GKT School of Medicine, London.)
| 100 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
54 SECTION 1
fibres. B fibres are myelinated autonomic preganglionic efferent fibres.
C fibres are unmyelinated and have thermoreceptive, nociceptive and
interoceptive functions, including the perception of slow, burning pain
and visceral pain. This scheme can be applied to fibres of both spinal
and cranial nerves except perhaps those of the olfactory nerve, where
the fibres form a uniquely small and slow group. The largest somatic
efferent fibres (A α) innervate extrafusal muscle fibres (at motor end-
plates) exclusively and conduct at a maximum of 120 m/s. Fibres to fast
twitch muscles are larger than those to slow twitch muscle. Smaller (A γ)
fibres of gamma motor neurones, and autonomic preganglionic (B) and postganglionic (C) efferent fibres conduct, in order, progressively more
slowly (40 m/s to less than 10 m/s).
A different classification, used for afferent fibres from muscles,
divides fibres into groups I–IV on the basis of their calibre; groups I–III are myelinated and group IV is unmyelinated. Group I fibres are large
(12–22 µm), and include primary sensory fibres of muscle spindles
(group Ia) and smaller fibres of Golgi tendon organs (group Ib). Group II fibres are the secondary sensory terminals of muscle spindles, with
diameters of 6–12 µm. Group III fibres, 1–6 µm in diameter, have free
sensory endings in the connective tissue sheaths around and within muscles and are nociceptive and, in skin, also thermosensitive. Group
IV fibres are unmyelinated, with diameters below 1.5 µm; they include
free endings in skin and muscle, and are primarily nociceptive.
CONNECTIVE TISSUE SHEATHS
Nerve trunks, whether uni- or multifascicular, are limited externally by
an epineurium, which is connected to surrounding tissues by mesoneu-
rium. Mesoneurium is a loose connective tissue sheath (see Ch. 2)
containing the extrinsic, segmental blood supply of the nerve, and so is of clinical importance in nerve injury. Individual fasciculi of the nerve
trunk are enclosed by a multilayered perineurium, which in turn sur -
rounds the endoneurium or intrafascicular connective tissue (see
Fig. 3.20).
Epineurium
Epineurium is a condensation of loose (areolar) connective tissue derived from mesoderm. As a general rule, the more fasciculi present
in a peripheral nerve, the thicker the epineurium. Epineurium contains
fibroblasts, collagen (types I and III) and variable amounts of fat, and
it cushions the nerve it surrounds. Loss of this protective layer may be
associated with pressure palsies seen in wasted, bedridden patients. The
epineurium also contains lymphatics (which probably pass to regional
lymph nodes) and blood vessels, vasa nervorum, that pass across the
perineurium to communicate with a network of fine vessels within the
endoneurium, forming the intrinsic system of vascular plexuses.
Perineurium
Perineurium extends from the CNS–PNS transition zone to the periph -
ery, where it is continuous with the capsules of muscle spindles and encapsulated sensory endings, but ends openly at unencapsulated
endings and neuromuscular junctions. It consists of alternating layers
of flattened polygonal cells (thought to be derived from fibroblasts) and
collagen. It can often contain 15–20 layers of such cells, each layer
enclosed by a basal lamina up to 0.5 µm thick. Within each layer the
cells interdigitate along extensive tight junctions; their cytoplasm typi -
cally contains vesicles and bundles of microfilaments and their plasma membrane often shows evidence of pinocytosis. These features are con -
sistent with the function of the perineurium as a metabolically active diffusion barrier; together with the blood–nerve barrier, the perineu -
rium is thought to play an essential role in maintaining the osmotic milieu and fluid pressure within the endoneurium. Lymphatic vessels
have not been detected in the perineurium.
Endoneurium
Strictly speaking, the term endoneurium is restricted to intrafascicular
connective tissue and excludes the perineurial partitions within fasci -
cles. Endoneurium consists of a fibrous matrix composed predomi -
nantly of type III collagen (reticulin) fibres, characteristically organized
in fine bundles lying parallel to the long axis of the nerve, and con -
densed around individual Schwann cell–axon units and endoneurial vessels. The fibrous and cellular components of the endoneurium are bathed in endoneurial fluid at a slightly higher pressure than that outside in the surrounding epineurium. The major cellular constituents Monocytes enter the CNS in the early stages of infarction and
autoimmune disease and, in particular, in pyogenic infections, probably
by passing through the endothelium of local vessels. Once in the brain,
monocytes are difficult to distinguish from intrinsic microglia because
both cell types express a similar marker profile. During the inflamma -
tory phase of meningitis, polymorphonuclear leukocytes and lym -
phocytes pass into the CSF through the endothelium of large veins in
the subarachnoid space. Recent developments in research on brain
inflammatory disorders are reviewed in Anthony and Pitossi (2013).
PERIPHERAL NERVES
Afferent nerve fibres connect peripheral receptors to the CNS; they are derived from neuronal somata located either in special sense organs
(e.g. the olfactory epithelium) or in the sensory ganglia of the cranio -
spinal nerves. Efferent nerve fibres connect the CNS to the effector cells and tissues and are the peripheral axons of neurones with somata in
the central grey matter.
Peripheral nerve fibres are grouped in widely variable numbers into
bundles (fasciculi). The size, number and pattern of fasciculi vary in
different nerves and at different levels along their paths ( Fig. 3.20).
Their number increases and their size decreases some distance proximal to a point of branching. Where nerves are subjected to pressure, e.g.
deep to a retinaculum, fasciculi are increased in number but reduced
in size, and the amount of associated connective tissue and degree of
vascularity also increase. At these points, nerves may occasionally show
a pink, fusiform dilation, sometimes termed a pseudoganglion or gan-
gliform enlargement.
CLASSIFICATION OF PERIPHERAL NERVE FIBRES
Classification of peripheral nerve fibres is based on various parameters
such as conduction velocity, function and fibre diameter. Of two clas -
sifications in common use, the first divides fibres into three major classes, designated A, B and C, corresponding to peaks in the distribu -
tion of their conduction velocities. In humans, this classification is used mainly for afferent fibres from the skin. Group A fibres are subdivided
into α, β, γ and δ subgroups; fibre diameter and conduction velocity
are proportional in most fibres. Group A α fibres are the largest and
conduct most rapidly, and C fibres are the smallest and slowest.
The largest afferent axons (A α fibres) innervate encapsulated cutane -
ous mechanoreceptors, Golgi tendon organs and muscle spindles, and
some large alimentary enteroceptors. Aβ fibres form secondary endings
on some muscle spindle (intrafusal) fibres and also innervate cutaneous
and joint capsule mechanoreceptors. Aδ fibres innervate thermorecep-
tors, stretch-sensitive free endings, hair receptors and nociceptors,
including those in dental pulp, skin and connective tissue. A γ fibres are
exclusively fusimotor to plate and trail endings on intrafusal muscle
Fig. 3.20 A transverse section of a biopsied human sural nerve, showing
the arrangement of the connective tissue sheaths. Individual axons,
myelinated and unmyelinated, are arranged in a small fascicle bounded by a perineurium. Abbreviations: P, perineurium; Ep, epineurium;
E, endoneurium. (Courtesy of Professor Susan Standring, GKT School
of Medicine, London.)
EP
Ep | 101 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Peripheral nerves
55
CHAPTER 3
et al 2008). The region under the compact myelin sheath that extends
between two juxtaparanodes is the internode. The molecular domains
of myelinated axons, including that of the axon initial segment are
reviewed in Buttermore et al (2013)).
Schwann cell cytoplasm forms a continuous layer only in the peri -
nuclear (mid-internodal) and paranodal regions, where it forms a collar
from which microvilli project into the nodal gap substance. Elsewhere
it is dispersed as a lace-like network over the inner (adaxonal) and outer
(abaxonal) surfaces of the myelin sheath.
Nodes of Ranvier
The nodal compartment consists of a short length of exposed axo -
lemma, typically 0.8–1.1 µm long, surrounded by a nodal gap sub -
stance composed of various extracellular components, some of which may possess nerve growth-repulsive characteristics. Multiple processes
(microvilli) protrude into the gap substance from the outer collar of
Schwann cytoplasm and contact the nodal axolemma. Voltage-gated
Na
+ channels, the cell adhesion molecules NrCAM and neurofascin-186,
the cytoskeletal adaptor ankyrin G25,26 and the actin-binding protein
spectrin βIV are clustered at nodes. The calibre of the nodal axon is
usually significantly less than that of the internodal axon, particularly in large-calibre fibres.
Paranodes
The axolemma on either side of a node is contacted by paranodal loops
of Schwann cell cytoplasm via specialized septate junctions that spiral
around the axon. The junctions are thought to form a partial diffusion
barrier into the peri-axonal space; restrict the movement of K+ channels
from under the compact myelin; and limit lateral diffusion of mem -
brane components. Caspr, contactin and their putative ligand NF155 (an isoform of neurofascin) are concentrated in paranodes.
Juxtaparanodes
The region of the axon lying just beyond the innermost paranodal junc -
tion is now recognized as a distinct domain defined by the localization
of voltage-gated K+ channels (delayed-rectifier K+ channels Kv1.1, Kv1.2
and their Kvb2 subunit). Clustering of Kv1 channels at the juxtapara -
nodal region depends on their association with the Caspr2/TAG-1 adhe -
sion complex.
Schmidt–Lanterman incisures
Schmidt–Lanterman incisures are helical decompactions of internodal
myelin that appear as funnel-like profiles in teased fibre preparations labelled for markers of non-compacted myelin (e.g. MAG, Cx32). At an incisure the major dense line of the myelin sheath splits to enclose a continuous spiral band of cytoplasm passing between abaxonal and adaxonal layers of Schwann cell cytoplasm. The minor dense line of incisural myelin is also split, creating a channel connecting the peri-axonal space with the endoneurial extracellular fluid. The function of of the endoneurium are Schwann cells and endothelial cells; minor
components are fibroblasts (constituting approximately 4% of the total
endoneurial cell population), resident macrophages and mast cells.
Schwann cell–axon units and blood vessels are enclosed within indi -
vidual basal laminae and therefore isolated from the other cellular and extracellular components of the endoneurium.
Endoneurial arterioles have a poorly developed smooth muscle layer
and do not autoregulate well. In sharp contrast, epineurial and perineu -
rial vessels have a dense perivascular plexus of peptidergic, serotonin -
ergic and adrenergic nerves. There are free nerve endings in all layers of
neural connective tissue sheaths and there are some encapsulated
(Pacinian) corpuscles in the endoneurium. These probably contribute
to the acute sensitivity of nerves trapped in fibrosis after injury or
surgery.
SCHWANN CELLS
Schwann cells are the major glial type in the PNS. In vitro they are
fusiform in appearance. Both in vitro and in vivo, Schwann cells ensheathe
peripheral axons, and myelinate those greater than 2 µm in diameter.
In a mature peripheral nerve, they are distributed along the axons in
longitudinal chains; the geometry of their association depends on
whether the axon is myelinated or unmyelinated. In myelinated axons
the territory of a Schwann cell defines an internode.
The molecular phenotype of mature myelin-forming Schwann cells
is different from that of mature non-myelin-forming Schwann cells.
Adult myelin-forming Schwann cells are characterized by the presence
of several myelin proteins, some, but not all, of which are shared with
oligodendrocytes and central myelin. In contrast, expression of the
low-affinity neurotrophin receptor (p75NTR) and GFAP intermediate
filament protein (which differs from the CNS form in its post-translational modification) characterizes adult non-myelin-forming
Schwann cells.
Schwann cells arise from Schwann cell precursors that, in turn, are
generated from multipotent cells of the neural crest. Neuronal signals
regulate many aspects of Schwann cell behaviour in developing and
postnatal nerves. Axon-associated signals appear to control the prolif -
eration of developing Schwann cells and their precursors; the develop -
mentally programmed death of those precursors in order to match
numbers of axons and glia within each peripheral nerve bundle; the
production of basal laminae by Schwann cells; and the induction and
maintenance of myelination. Axonal neuregulin 1 signalling via ErbB2/
B3 receptors on Schwann cells is essential for Schwann cell myelination
and also determines myelin thickness. An extensive literature supports
the view that Schwann cells are key players in the acute injury response
in the PNS (see Commentary 1.6 ), helping to provide a microenviron -
ment that facilitates axonal regrowth (Birch 201 1). Few Schwann cells persist in chronically denervated nerves. For further reading about
Schwann cells, see Kidd et al (2013).
Unmyelinated axons
Unmyelinated axons are commonly 1.0 µm in diameter, although some
may be 1.5 µm or even 2 µm in diameter. Groups of up to 10 or more
small axons (0.15–2.0 µm in diameter) are enclosed within a chain of
overlapping Schwann cells that is surrounded by a basal lamina. Within each Schwann cell, individual axons are usually sequestered from their
neighbours by delicate processes of cytoplasm. It seems likely, on the
basis of quantitative studies in subhuman primates, that axons from
adjacent cord segments may share Schwann cell columns; this phenom -
enon may play a role in the evolution of neuropathic pain after nerve injury. In the absence of a myelin sheath and nodes of Ranvier, action
potential propagation along unmyelinated axons is not saltatory but
continuous, and relatively slow (0.5–4.0 m/s).
Myelinated axons
Myelinated axons (Fig. 3.21 ) have a 1 : 1 relationship with their
ensheathing Schwann cells. The territorial extent of individual Schwann
cells varies directly with the diameter of the axon they surround, from
150 to 1500 µm. Specialized domains of axo-glial interaction define
nodes of Ranvier and their neighbouring compartments, paranodes and
juxtaparanodes (Pereira et al 2012; Fig. 3.22). These domains contain
multiprotein complexes characterized by unique sets of transmembrane and cytoskeletal proteins and clusters of ion channels; the mechanisms regulating channel clustering and node formation remain a subject of intense scrutiny (Peles and Salzer 2000, Poliak and Peles 2003, Horresh
Fig. 3.21 An electron micrograph of a transverse section of biopsied
human sural nerve, showing a myelinated axon and several unmyelinated
axons (A), ensheathed by Schwann cells (S). (Courtesy of Professor Susan
Standring, GKT School of Medicine, London.)
S
SA
A
A | 102 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
56 SECTION 1
from horizontal basal stem cells in the olfactory epithelium (Leung et al
2007, Forni and Wray 2012). They extend new axons through the
lamina propria and cribriform plate into the CNS environment of the
olfactory bulb, where they synapse with second-order neurones. Olfac -
tory ensheathing cells (OECs, also known as olfactory ensheathing glia) accompany olfactory axons from the lamina propria of the olfactory
epithelium to their synaptic contacts in the glomeruli of the olfactory
bulbs and are thought to play a role in directing them to their correct
position in the olfactory bulb (Higginson and Barnett 201 1). This
unusual arrangement is unique; elsewhere in the nervous system the
territories of peripheral and central glia are clearly demarcated at CNS–
PNS transition zones. OECs and the end-feet of astrocytes lying between
the bundles of olfactory axons both contribute to the glia limitans at
the pial surface of the olfactory bulbs.
OECs share many properties with Schwann cells and express similar
antigenic and morphological properties. They ensheathe olfactory
sensory axons in a manner comparable to the relationship that exists
transitorily between Schwann cells and axons in very immature periph -
eral nerves, i.e. they surround, but do not segregate, bundles of up to 50 fine unmyelinated axons to form approximately 20 fila olfactoria.
Both OECs and Schwann cells can myelinate axons, even though nor -
mally none of the axons in the olfactory nerve is myelinated. It was
thought that OECs shared a common origin with olfactory receptor neurones in the olfactory placode, but recent fate-mapping experiments in chicken embryos and genetic linkage-tracing studies in mice have shown that OECs are derived from neural crest cells (Forni and Wray 2012).
OECs have a malleable phenotype. There may be several subtypes:
some OECs express GFAP as either fine filaments or more diffusely in their cytoplasm, and some express p75
NTR and the O4 antigen.incisures is not known; their structure suggests that they may participate
in transport of molecules across the myelin sheath.
SATELLITE CELLS
Many non-neuronal cells of the nervous system have been called satel -
lite cells, including small, round extracapsular cells in peripheral ganglia, ganglionic capsular cells, Schwann cells, any cell that is closely
associated with neuronal somata, and precursor cells associated with
striated muscle fibres (Hanani 2010). Within the nervous system, the
term is most commonly reserved for flat, epithelioid cells (ganglionic
glial cells, capsular cells) that surround the neuronal somata of periph -
eral ganglia (see Fig. 3.23). Their cytoplasm resembles that of Schwann
cells, and their deep surfaces interdigitate with reciprocal infoldings in
the membranes of the enclosed neurones.
Enteric glia
Enteric nerves lack an endoneurium and so do not have the collagenous coats of other peripheral nerves. The enteric ganglionic neurones are
supported by glia that closely resemble astrocytes; they contain more
GFAP than non-myelinating Schwann cells and do not produce a basal
lamina. Evidence for their roles in gut function is reviewed in Gul-
bransen and Sharkey (2012).
Olfactory ensheathing glia
The olfactory system is unusual because it supports neurogenesis throughout life. Olfactory receptor neurones are continuously renewed Fig. 3.22 The general plan of a peripheral myelinated nerve fibre in longitudinal section, including one complete internodal segment and two adjacent
paranodal bulbs, used as a key for the more detailed microarchitecture of specific subregions. A, A transverse electron microscope section through the
centre of a node of Ranvier, with numerous finger-like processes of adjacent Schwann cells converging towards the nodal axolemma. Many microtubules
and neurofilaments are visible within the axoplasm. B, The arrangement of the axon, myelin sheath and Schwann cell cytoplasm at the node of Ranvier,
in the paranodal bulbs and in the juxtaparanodal region. The axon is myelinated by a Schwann cell surrounded by a basal lamina (BL). Only a portion of the internode, which is located beneath the compact myelin (CM) sheath, is shown. A spiral of paranodal (green) and juxtaparanodal (blue) proteins
extends into the internode; this spiral is apposed to the inner mesaxon of the myelin sheath (not shown). K
+ channels and Caspr2 are concentrated in the
juxtaparanodal region. In the paranodal region, the compact myelin sheath opens up into a series of paranodal cytoplasmic loops (PNL) that invaginate
and closely appose the axon, forming a series of septum-like junctions that spiral around the axon. Caspr, contactin and an isoform of neurofascin
(NF155) are concentrated in this region. At the node, numerous microvilli (MV) project from the outer collar of the Schwann cell to contact the axolemma.
The axon is enormously enriched in intramembranous particles at the node that correspond to Na+ channels (Na+ ch). Ankyrin G (ank G) isoforms and the
cell adhesion molecules NrCAM and NF186 are also concentrated in this region. (A, Courtesy of Professor Susan Standring, GKT School of Medicine,
London. B, Redrawn from Peles and Salzer 2000.)
MV
Internode Juxtaparanode
• Caspr 2• Kv1.1, 1.2, β2Paranode• Caspr• Contactin• NF155Node• Na
+ ch
• ank G• NrCAM• NF186PNL PNL PNLCM
CM
EPBLB A | 103 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Peripheral nerves
57
CHAPTER 3
processes; in myelinated fibres the junction occurs at a node of Ranvier.
The peripheral process terminates in a sensory ending and, because it
conducts impulses towards the soma, it functions as an elongated den -
drite, strictly speaking. However, it has the typical structural and func -
tional properties of a peripheral axon, and is conventionally described
as an axon.
Each neuronal soma is surrounded by a sheath of satellite glial cells
(SGCs). (A notable exception is the spiral, or cochlear, ganglion, where
most neuronal somata are myelinated, presumably contributing to fast
electrical transmission.) The axodendritic process and its peripheral and
central divisions, ensheathed by Schwann cells, lie outside the SGC
sheath. All the cells in the ganglion lie within a highly vascularized
connective tissue that is continuous with the endoneurium of the nerve
root. In dorsal root ganglia there is no clear regional mapping of the
innervated body regions. In contrast, each of the three nerve branches
(ophthalmic, maxillary and mandibular) of the trigeminal nerve is
mapped to a different part of the trigeminal ganglion. Although sensory
neurones receive no synapses, they are endowed with receptors for
numerous neurotransmitters and hormones, and can thus communi -
cate chemically amongst themselves and with SGCs.
SGCs are the main type of glial cell in sensory ganglia. They share
several properties with astrocytes, including expression of glutamine synthetase and various neurotransmitter transporters. In addition, like
astrocytes, the SGCs that surround a neurone are coupled by gap junc -
tions and express receptors for ATP. Unlike astrocytes, SGCs completely surround individual sensory neurones (and more rarely two or three
neurons) in a glial sheath. They undergo major changes as a result of
injury to peripheral nerves, and appear to contribute to chronic pain in
a number of animal pain models.
Herpes zoster Primary infection with the varicella zoster virus causes
chickenpox. Following recovery, the virus remains dormant within dorsal root ganglia or trigeminal ganglia, mostly in the neurones, and
less commonly in the SGCs. Reactivation of the virus leads to herpes
zoster (shingles), which involves the dermatome(s) supplied by the
affected sensory nerve(s). Diagnostic signs are severe pain, erythema
and blistering as occurs in chickenpox, often confined to one of the
divisions of the trigeminal nerve or to a spinal nerve dermatome.
Herpes zoster involving the geniculate ganglion compresses the facial
nerve and results in a lower motor neurone facial paralysis, known as
Ramsay Hunt syndrome. Occasionally, if the vestibulocochlear nerve
becomes involved, there is vertigo, tinnitus and some deafness. The
most important complication of herpes zoster is post-herpetic neural -
gia, a severe and persistent pain that is highly refractory to treatment.
Autonomic ganglia
The main types of cell in autonomic ganglia are the ganglionic neu -
rones, small intensely fluorescent (SIF) cells and satellite glial cells
(SGCs). Most of the neurones have somata ranging from 25 to 50 µm
and complex dendritic fields; dendritic glomeruli have been observed in ganglia in experimental animals. Ganglionic neurones receive many
axodendritic synapses from preganglionic axons; axosomatic synapses
are less numerous. Postganglionic fibres commonly arise from the
initial stem of a large dendrite and produce few or no collateral proc -
esses. Given their close relationship to the ganglionic neurones, auto -
nomic SGCs may have the potential to influence synaptic transmission.
SIF cells are characterized by being smaller than the neurones and by
having numerous granules that contain noradrenaline (norepine-
phrine), dopamine and serotonin. They are almost completely invested
by a sheath of SGCs and receive and make synapses; their physiological
role is currently obscure, but they lend credence to the idea that auto -
nomic ganglia are far more than simple relay stations.
Sympathetic neurones are multipolar and their dendritic trees, on
which preganglionic motor axons synapse, are more elaborate than those of parasympathetic neurones (Fig. 3.24). The neurones are sur-
rounded by a mixed neuropil of afferent and efferent fibres, dendrites,
synapses and non-neural cells. There is considerable variation in the
ratio of pre- and postganglionic fibres in different types of ganglion.
Preganglionic sympathetic axons may synapse with many postgangli -
onic neurones for the wide dissemination and perhaps amplification of
sympathetic activity, a feature not found to the same degree in para -
sympathetic ganglia. Dissemination may also be achieved by connec -
tions with ganglionic interneurones or by the diffusion within the ganglion of transmitter substances produced either locally (paracrine effect) or elsewhere (endocrine effect). Some axons within a ganglion may be efferent fibres en route to another ganglion, or afferents from viscera and glands. These fibres may synapse with neurones in the BLOOD SUPPLY OF PERIPHERAL NERVES
The blood vessels supplying a nerve, end in a capillary plexus that
pierces the perineurium. The branches of the plexus run parallel with
the fibres, connected by short transverse vessels, forming narrow, rec -
tangular meshes similar to those found in muscle. The blood supply of peripheral nerves is unusual. Endoneurial capillaries have atypically
large diameters and intercapillary distances are greater than in many
other tissues. Peripheral nerves have two separate, functionally inde -
pendent vascular systems: an extrinsic system (regional nutritive vessels and epineurial vessels) and an intrinsic system (longitudinally running
microvessels in the endoneurium). Anastomoses between the two
systems produce considerable overlap between the territories of the
segmental arteries. This unique pattern of vessels, together with a high
basal nerve blood flow relative to metabolic requirements, means that
peripheral nerves possess a high degree of resistance to ischaemia.
Blood–nerve barrier
Just as the neuropil within the CNS is protected by a blood–brain barrier, the endoneurial contents of peripheral nerve fibres are protected
by a blood–nerve barrier and by the cells of the perineurium. The
blood–nerve barrier operates at the level of the endoneurial capillary
walls, where the endothelial cells are joined by tight junctions, and are
non-fenestrated and surrounded by continuous basal laminae. The
barrier is much less efficient in dorsal root ganglia and autonomic
ganglia and in the distal parts of peripheral nerves.
GANGLIA
Ganglia are aggregations of neuronal somata and are of varying form and size. They occur in the dorsal roots of spinal nerves; in the sensory
roots of the trigeminal, facial, vestibulocochlear, glossopharyngeal and
vagal cranial nerves; and in the peripheral autonomic nervous system
(ANS). Each ganglion is enclosed within a capsule of fibrous connective
tissue and contains neuronal somata and neuronal processes. Enteric
ganglia are an exception to this rule; they resemble the CNS in both
structure and function, and are not covered by a connective tissue
capsule. Some ganglia, particularly in the ANS, contain axons that
originate from neuronal somata that lie elsewhere in the nervous system
and which pass through the ganglia without synapsing.
Sensory ganglia
The sensory ganglia of dorsal spinal roots (Fig. 3.23) and the ganglia of the trigeminal, facial, glossopharyngeal and vagal cranial nerves are
enclosed in a periganglionic connective tissue capsule that resembles
the perineurium surrounding peripheral nerves. Ganglionic neurones
are unipolar (sometimes called pseudounipolar, see above). They have
spherical or oval somata of varying size, aggregated in groups between
fasciculi of myelinated and unmyelinated nerve fibres. For each neurone,
a single axodendritic process bifurcates into central and peripheral
Fig. 3.23 Sensory neurones in a dorsal root ganglion (rat). Neurones (N)
are typically variable in size but all are encapsulated by satellite cells (S).
Myelinated axons are seen above and below the neuronal somata. Toluidine blue stained resin section. (Courtesy of Dr Clare Farmer, King’s College, London.)
N
SS | 104 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
58 SECTION 1
the neonatal period. Treatment usually consists of removing the dis -
eased intestinal segment.
The enteric plexuses consist of sensory neurones, interneurones and
a variety of motor neurones. These neurones are endowed with recep -
tors for a large number of neurotransmitters and also release a variety
of neurotransmitters. All classes of enteric neurone are equally distrib -
uted along the entire ganglionic network; consequently the ENS con -
sists of numerous repeating modules.
The myenteric plexus contains the motor neurones that control the
movements of gastrointestinal smooth muscle. The main excitatory
neurotransmitter is acetylcholine, which may be co-localized with an
excitatory peptide (usually a tachykinin, such as substance P). The main
inhibitory neurotransmitter is nitric oxide (NO), released from neu-
rones that may also release the inhibitory peptide vasoactive intestinal
peptide (VIP).
An important function of myenteric neurones is to mediate the peri -
staltic reflex, which is induced by intestinal wall distension or by
mechanical stimulation of the mucosa. These stimuli initiate contrac -
tion oral to the site of the stimulus, and relaxation anal to the site, creat -
ing a pressure gradient that propels the intestinal contents. Interstitial
cells of Cajal (ICC) are pacemaker cells believed to integrate neuronal
signals with rhythmic oscillations of muscle contraction; disturbance of
ICC function may be a factor in a number of gastrointestinal disorders
(Huizinga et al 2009).
Enteric glia are the main type of glial cell in the ENS. In some
respects they resemble astrocytes, e.g. they form end-feet with blood vessels, respond to numerous chemical mediators, and are extensively
coupled among themselves by gap junctions. They appear to play an
important role in neuroprotection and in maintaining the integrity of
the intestinal mucosal barrier.
DISPERSED NEUROENDOCRINE SYSTEM
Although the nervous, neuroendocrine and endocrine systems all
operate by intercellular communication, they differ in the mode, speed
and degree or localization of the effects produced (Day and Salzet
2002). The autonomic nervous system uses impulse conduction and
neurotransmitter release to transmit information, and the responses
induced are rapid and localized. The dispersed neuroendocrine system
uses only secretion. It is slower and the induced responses are less local -
ized, because the secretions, e.g. neuromediators, can act either on contiguous cells, or on groups of nearby cells reached by diffusion, or
on distant cells via the blood stream. Many of its effector molecules
operate in both the nervous system and the neuroendocrine system.
The endocrine system proper, which consists of clusters of cells and
discrete, ductless, hormone-producing glands, is even slower and less
localized, although its effects are specific and often prolonged. These
regulatory systems overlap in function, and can be considered as a
single neuroendocrine regulator of the metabolic activities and internal
environment of the organism, acting to provide conditions in which it
can function successfully. Neural and neuroendocrine axes appear to
cooperate to modulate some forms of immunological reaction; the
extensive system of vessels, circulating hormones and nerve fibres that
link the brain with all viscera are thought to constitute a neuroimmune
network (Fig. 3.26).
Some cells can take up and decarboxylate amine precursor com -
pounds (amine precursor uptake and decarboxylation, or APUD, cells).
They are characterized by dense-core cytoplasmic granules (see Fig. 2.6),
similar to the neurotransmitter vesicles seen in some types of neuronal terminal. The group includes cells described as chromaffin cells (phaeo -
chromocytes), derived from neuroectoderm and innervated by pregan -
glionic sympathetic nerve fibres. Chromaffin cells synthesize and secrete
catecholamines (dopamine, noradrenaline (norepinephrine) or adren -
aline (epinephrine)). Their name refers to the finding that their cyto -
plasmic store of catecholamines is sufficiently concentrated to give an
intense yellow–brown colouration, the positive chromaffin reaction,
when they are treated with aqueous solutions of chromium salts, par -
ticularly potassium dichromate. Classic chromaffin cells include clus-ters of cells in the suprarenal medulla; the para-aortic bodies, which
secrete noradrenaline; paraganglia; certain cells in the carotid bodies;
and small groups of cells irregularly dispersed among the paravertebral
sympathetic ganglia, splanchnic nerves and prevertebral autonomic plexuses.
The alimentary tract contains a large population of cells of a similar
type (previously called neuroendocrine or enterochromaffin cells)
in its wall. These cells act as sensory transducers, activating intrinsic
and extrinsic primary afferent neurones via their release of 5-
hydroxytryptamine (5-HT, serotonin). The neonatal respiratory tract
ganglion, e.g. substance P-containing axons of dorsal root neurones
synapse on neurones in prevertebral ganglia, thereby enabling interac -
tions between the sensory system and the ANS.
Enteric ganglia
The enteric nervous system (ENS) lies within the walls of the gastroin-testinal tract (see Fig. 2.15 for the layers of a typical viscus) and includes
the myenteric and submucosal plexuses and associated ganglia (Furness
2012, Neunlist et al 2013). The ganglionic neurones ( Fig. 3.25) serve
different functions, including the regulation of gut motility (in conjunc -
tion with interstitial cells of Cajal (Huizinga et al 2009)), mucosal
transport and mucosal blood flow. Unlike the other two divisions of the ANS, the ENS is largely independent of the CNS, and the extrinsic
autonomic fibres that supply the gut wall exert only modulatory effects
on it. Submucosal neurones, together with sympathetic axons, regulate
the local blood flow.
Hirschsprung’s disease is a congenital disease in which dysfunctional
neural crest migration means that the ganglia of both the myenteric and submucosal plexuses in the distal bowel fail to develop. The resulting lack of propulsive activity in the aganglionic bowel leads to functional obstruction and megacolon, which can be life-threatening. Around 1 in 5,000 infants is born with the condition and is typically diagnosed in Fig. 3.24 A parasympathetic autonomic ganglion from a human stomach.
Large neuronal somata, some with nuclei and prominent nucleoli in the
plane of section, are encapsulated by satellite cells and surrounded by
nerve fibres and non-neuronal cells. (Courtesy of Mr Peter Helliwell and
the late Dr Joseph Mathew, Department of Histopathology, Royal
Cornwall Hospitals Trust, UK.)
Fig. 3.25 An enteric ganglion (outlined) of the myenteric (Auerbach’s)
plexus between the inner circular and outer longitudinal layers of smooth
muscle (M) in the wall of the human intestine. An enteric ganglionic
neurone is arrowed. (Courtesy of Mr Peter Helliwell and the late Dr
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
Trust, UK.)
MM | 105 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Sensory endings
59
CHAPTER 3
receptor and partly in the neurone that innervates it, in the case of
epithelial receptors. Transduction varies with the modality of the stimu -
lus, and usually causes depolarization of the receptor membrane (or hyperpolarization, in the retina). In mechanoreceptors, transduction
may involve the deformation of membrane structure, which causes
either strain or stretch-sensitive ion channels to open. In chemorecep -
tors, receptor action may resemble that for ACh at neuromuscular
junctions. Visual receptors share similarities with chemoreceptors:
light causes changes in receptor proteins, which activate G proteins, resulting in the release of second messengers and altered membrane
permeability.
The quantitative responses of sensory endings to stimuli vary greatly
and increase the flexibility of the functional design of sensory systems.
Although increased excitation with increasing stimulus level is a
common pattern (‘on’ response), some receptors respond to decreased
stimulation (‘off’ response). Even unstimulated receptors show varying
degrees of spontaneous background activity against which an increase
or decrease in activity occurs with changing levels of stimulus. In all
receptors studied, when stimulation is maintained at a steady level,
there is an initial burst (the dynamic phase) followed by a gradual
adaptation to steady level (the static phase). Though all receptors show
these two phases, one or other may predominate, providing a distinc -
tion between rapidly adapting endings that accurately record the rate of stimulus onset, and slowly adapting endings that signal the constant
amplitude of a stimulus, e.g. position sense. Dynamic and static phases
are reflected in the amplitude and duration of the receptor potential
and also in the frequency of action potentials in the sensory fibres. The
stimulus strength necessary to elicit a response in a receptor, i.e. its
threshold level, varies greatly between receptors, and provides an extra
level of information about stimulus strength.
For further information on sensory receptors, see Nolte (2008).
FUNCTIONAL CLASSIFICATION OF RECEPTORS
Receptors have been classified in several ways. They may be classified by the modalities to which they are sensitive, such as mechanoreceptors
(which are responsive to deformation, e.g. touch, pressure, sound waves,
etc.), chemoreceptors, photoreceptors and thermoreceptors. Some re -
ceptors are polymodal, i.e. they respond selectively to more than one modality; they usually have high thresholds and respond to damaging
stimuli associated with irritation or pain (nociceptors).
Another widely used classification divides receptors on the basis of
their distribution in the body into exteroceptors, proprioceptors and
interoceptors. Exteroceptors and proprioceptors are receptors of the
somatic afferent components of the nervous system, while interoceptors
are receptors of the visceral afferent pathways.
Exteroceptors respond to external stimuli and are found at, or close
to, body surfaces. They can be subdivided into the general or cutaneous
sense organs and special sensory organs. General sensory receptors
include free and encapsulated terminals in skin and near hairs; none
of these has absolute specificity for a particular sensory modality.
Special sensory organs are the olfactory, visual, acoustic, vestibular and
taste receptors.
Proprioceptors respond to stimuli to deeper tissues, especially of the
locomotor system, and are concerned with detecting movement,
mechanical stresses and position. They include Golgi tendon organs,
muscle spindles, Pacinian corpuscles, other endings in joints, and ves -
tibular receptors. Proprioceptors are stimulated by the contraction of muscles, movements of joints and changes in the position of the body.
They are essential for the coordination of muscles, the grading of mus -
cular contraction, and the maintenance of equilibrium.
Interoceptors are found in the walls of the viscera, glands and vessels,
where their terminations include free nerve endings, encapsulated ter -
minals and endings associated with specialized epithelial cells. Nerve
terminals are found in the layers of visceral walls and the adventitia of
blood vessels, but the detailed structure and function of many of these
endings are not well established. Encapsulated (lamellated) endings
occur in the heart, adventitia and mesenteries. Free terminal arboriza -
tions occur in the endocardium, the endomysium of all muscles, and connective tissue generally. Tension produced by excessive muscular
contraction or by visceral distension often causes pain, particularly in
pathological states, which is frequently poorly localized and of a deep-seated nature. Visceral pain is often referred to the corresponding der -
matome (see Fig. 16.10). Polymodal nociceptors (irritant receptors)
respond to a variety of stimuli such as noxious chemicals or damaging mechanical stimuli. They are mainly the free endings of fine, unmyeli -
nated fibres that are widely distributed in the epithelia of the alimentary and respiratory tracts; they may initiate protective reflexes.contains a prominent system of neuroendocrine cells, both dispersed
and aggregated (neuroepithelial bodies); the numbers of both types
decline during childhood. Merkel cells (see Commentary 1.3 ) in the
basal epidermis of the skin store neuropeptides, which they release
to associated nerve endings or other cells in a neuroendocrine role, in
response to pressure and possibly other stimuli (Lucarz and Brand
2007). Experimental animal studies have revealed 5-HT-containing
intraepithelial paraneurones in the urothelial lining of the urethra;
these cells are thought to relay information from the luminal surface
of the urethra to underlying sensory nerves.
A number of descriptions and terms have been applied to cells of
this system in the older literature (see online text for details).
For further reading, see Day and Salzet (2002).
SENSORY ENDINGS
GENERAL FEATURES OF SENSORY RECEPTORS
There are three major forms of sensory receptor: neuroepithelial, epi -
thelial and neuronal ( Fig. 3.27).
A neuroepithelial receptor is a neurone with a soma lying near a
sensory surface and an axon that conveys sensory signals into the CNS
to synapse on second-order neurones. This is an evolutionarily primi -
tive arrangement, and the only examples remaining in humans are the sensory neurones of the olfactory epithelium.
An epithelial receptor is a cell that is modified from a non-nervous
sensory epithelium and innervated by a primary sensory neurone with
a soma lying near the CNS, e.g. auditory receptors and taste buds. When
activated, this type of receptor excites its neurone by neurotransmission
across a synaptic gap.
A neuronal receptor is a primary sensory neurone that has a soma
in a craniospinal ganglion and a peripheral axon ending in a sensory
terminal. All cutaneous sensors and proprioceptors are of this type;
their sensory terminals may be encapsulated or linked to special meso -
dermal or ectodermal structures to form a part of the sensory apparatus.
The extraneural cells are not necessarily excitable, but create an appro -
priate environment for the excitation of the neuronal process.
The receptor stimulus is transduced into a graded change of electrical
potential at the receptor surface (receptor potential), and this initiates an all-or-none action potential that is transmitted to the CNS. This may occur either in the receptor, when this is a neurone, or partly in the
Fig. 3.26 The ways in which the nervous system, neuroendocrine system
and immune system are integrated, demonstrated in the intestine.
Neurocrine signals from enteric neuroendocrine cells and signals from
immune defence cells (e.g. lymphocytes, macrophages and mast cells)
act on other cells of those systems and on neurones with sensory
endings in the intestinal wall, either locally or at a distance. Some
neuronal soma lie within enteric ganglia in the gut wall; others have their
bodies in peripheral ganglia. Neuronal signals may act locally, be
transmitted to the CNS or enter a reflex pathway via sympathetic ganglia. Gut lumenImmune and tissue
defence signals:local and systemicIntestinofugal
neurone
Neurocrine signals:local and circulatingSpinal cordSpinal sensory neuronePrevertebral sympathetic ganglion
Intrinsic
sensory
neurone
StretchBrainstem
Sensory vagal neurone
Signals from lumen
e.g. nutrients, antigens,
irritants, secretions | 106 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Nervous system
59.e1
CHAPTER 3
They include: clear cells (so named because of their poor staining
properties in routine preparations); argentaffin cells (reduce silver
salts); argyrophil cells (absorb silver); small intensely fluorescent cells; peptide-producing cells (particularly of the hypothalamus, hypophysis, pineal and parathyroid glands, and placenta); Kulchitsky cells in the
lungs; and paraneurones. Many cells of the dispersed (or diffuse) neu-
roendocrine system are derived embryologically from the neural crest. Some – in particular, cells from the gastrointestinal system – are now known to be endodermal in origin. | 107 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
60 SECTION 1
Special types of free ending are associated with epidermal structures
in the skin. They include terminals associated with hair follicles (peri -
trichial receptors), which branch from myelinated fibres in the deep
dermal cutaneous plexus; the number, size and form of the endings are
related to the size and type of hair follicle innervated. These endings
respond mainly to movement when hair is deformed and belong to the
rapidly adapting mechanoreceptor group.
Merkel tactile endings (see Commentary 1.3) lie either at the base
of the epidermis or around the apical ends of some hair follicles, and
most are innervated by large myelinated axons. Each axon expands into
a disc that is applied closely to the base of a Merkel cell in the basal
layer of the epidermis. The cells are believed to be derived from the
epidermis, although a neural crest origin remains possible. They contain
many large (50–100 nm) dense-core vesicles, presumably containing
transmitters. Merkel endings are thought to be slow-adapting mech -
anoreceptors, responsive to sustained pressure and sensitive to the edges of applied objects. Their functions are controversial, however, and
likely to be more varied.
ENCAPSULATED ENDINGS
Encapsulated endings are a major group of special endings that includes
lamellated corpuscles of various kinds (e.g. Meissner’s, Pacinian), Golgi tendon organs, neuromuscular spindles and Ruffini endings (see Fig.
3.27). They exhibit considerable variety in their size, shape and distribu -
tion but share a common feature: namely, that each axon terminal is encapsulated by non-excitable cells (Proske and Gandevia 2012).
Interoceptors include vascular chemoreceptors, e.g. the carotid body,
and baroceptors, which are concerned with the regulation of blood flow
and pressure and the control of respiration.
FREE NERVE ENDINGS
Sensory endings that branch to form plexuses occur in many sites (see
Fig. 3.27). They occur in all connective tissues, including those of the
dermis, fasciae, capsules of organs, ligaments, tendons, adventitia of
blood vessels, meninges, articular capsules, periosteum, perichon -
drium, Haversian systems in bone, parietal peritoneum, walls of viscera and the endomysium of all types of muscle. They also innervate the
epithelium of the skin, cornea, buccal cavity, and the alimentary and
respiratory tracts and their associated glands. Within epithelia, free
sensory endings lack Schwann cell ensheathment and are enveloped
instead by epithelial cells. Afferent fibres from free terminals may be
myelinated or unmyelinated but are always of small diameter and low
conduction velocity. When afferent axons are myelinated, their termi -
nal arborizations lack a myelin sheath. These terminals serve several
sensory modalities. In the dermis, they may be responsive to moderate
cold or heat (thermoreceptors); light mechanical touch (mechanore -
ceptors); damaging heat, cold or deformation (unimodal nociceptors); and damaging stimuli of several kinds (polymodal nociceptors). Similar fibres in deeper tissues may also signal extreme conditions, which are experienced, as with all nociceptors, as ache or pain. Free endings in the cornea, dentine and periosteum may be exclusively nociceptive.Fig. 3.27 Some major types of sensory ending of general afferent fibres (omitting neuromuscular, neurotendinous and hair-related types). The traces
below each type of ending indicate (top) their response (firing rate (vertical lines) and adaption with time) to an appropriate stimulus (below) of the
duration indicated. The Pacinian corpuscle’s response to vibration (rapid sequence of on–off stimuli) is also shown. Free endings:
Rapidly adapting mechanoreceptor
Thermoreceptor (hot and cold)
Nociceptor
Rapidly adapting ‘field’ mechanoreceptor
(Meissner’s corpuscle)Rapidly adapting lamellated (Pacinian) corpuscle Type II Slowly adapting mechanoreceptor
(Ruffini ending)Type I Slowly adapting mechanoreceptor
(Merkel cell ending) | 108 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Sensory endings
61
CHAPTER 3
into the capsule or core, so that it is not clearly defined in mature cor -
puscles. The core consists of approximately 60 bilateral, compacted
lamellae lying on both sides of a central nerve terminal.
Each corpuscle is supplied by a myelinated axon, which initially
loses its myelin sheath and subsequently loses its ensheathing Schwann
cell at its junction with the core. The naked axon runs through the
central axis of the core and ends in a slightly expanded bulb. It is in
contact with the innermost core lamellae, is transversely oval and sends
short projections of unknown function into clefts in the lamellae. The
axon contains numerous large mitochondria, and minute vesicles,
approximately 5 nm in diameter, which aggregate opposite the clefts.
The cells of the capsule and core lamellae are thought to be specialized fibroblasts but some may be Schwann cells. Elastic fibrous tissue forms
an overall external capsule to the corpuscle. Pacinian corpuscles are
supplied by capillaries that accompany the axon as it enters the capsule.
Pacinian corpuscles act as very rapidly adapting mechanoreceptors.
They respond only to sudden disturbances and are especially sensitive
to very-high-frequency vibration. The rapidity may be partly due to the
lamellated capsule acting as a high pass frequency filter, damping slow
distortions by fluid movement between lamellar cells. Groups of cor -
puscles respond to pressure changes, e.g. on grasping or releasing an object.
Ruffini endings
Ruffini endings are slowly adapting mechanoreceptors. They are found in the dermis of thin, hairy skin, where they function as dermal stretch
receptors and are responsive to maintained stresses in dermal collagen.
They consist of the highly branched, unmyelinated endings of myeli -
nated afferents. They ramify between bundles of collagen fibres within a spindle-shaped structure, which is enclosed partly by a fibrocellular
sheath derived from the perineurium of the nerve. Ruffini endings
appear electrophysiologically similar to Golgi tendon organs, which
they resemble, although they are less organized structurally. Similar
structures appear in joint capsules (see below).
Golgi tendon organs
Golgi tendon organs are found mainly near musculotendinous junc -
tions (Fig. 3.30), where more than 50 may occur at any one site. Each
terminal is closely related to a group of muscle fibres (up to 20) as they
insert into the tendon. Golgi tendon organs are approximately 500 µm
long and 100 µm in diameter, and consist of small bundles of tendon Meissner’s corpuscles
Meissner’s corpuscles are found in the dermal papillae of all parts of the hand and foot, the anterior aspect of the forearm, the lips, palpebral
conjunctiva and mucous membrane of the apical part of the tongue.
They are most concentrated in thick hairless skin, especially of the finger
pads, where there may be up to 24 corpuscles per cm
2 in young adults.
Mature corpuscles are cylindrical in shape, approximately 80 µm long
and 30 µm across, with their long axes perpendicular to the skin surface.
Each corpuscle has a connective tissue capsule and central core com -
posed of a stack of flat modified Schwann cells ( Fig. 3.28). Meissner’s
corpuscles are rapidly adapting mechanoreceptors, sensitive to shape
and textural changes in exploratory and discriminatory touch; their acute sensitivity provides the neural basis for reading Braille text.
Pacinian corpuscles
Pacinian corpuscles are situated subcutaneously in the palmar and plantar aspects of the hand and foot and their digits, the external geni -
talia, arm, neck, nipple, periosteal and interosseous membranes, and near joints and within the mesenteries ( Fig. 3.29). They are oval, spheri -
cal or irregularly coiled and measure up to 2 mm in length and
100–500 µm or more across; the larger ones are visible to the naked
eye. Each corpuscle has a capsule, an intermediate growth zone and a
central core that contains an axon terminal. The capsule is formed by
approximately 30 concentrically arranged lamellae of flat cells approxi -
mately 0.2 µm thick (see Fig. 3.28). Adjacent cells overlap and succes -
sive lamellae are separated by an amorphous proteoglycan matrix that
contains circularly orientated collagen fibres, closely applied to the
surfaces of the lamellar cells. The amount of collagen increases with
age. The intermediate zone is cellular and its cells become incorporated
Fig. 3.28 A tactile Meissner’s corpuscle in a dermal papilla in the skin,
demonstrated using the modified Bielschowsky silver stain technique.
(Courtesy of Professor N Cauna, University of Pittsburgh.)
Epidermis
Tactile corpuscle
Fig. 3.29 A Pacinian corpuscle in human dermis. (Courtesy of Mr Peter
Helliwell and the late Dr Joseph Mathew, Department of Histopathology,
Royal Cornwall Hospitals Trust, UK.)
Fig. 3.30 The structure and innervation of a
Golgi tendon organ. For clarity, the perineurium
and endoneurium have been omitted to show
the distribution of nerve fibres ramifying
between the collagen fibre bundles of the
tendon. | 109 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
NERvOuS SySTEm
62 SECTION 1
acceleration. Moreover, they are under complex central control; efferent
(fusimotor) nerve fibres, by regulating the strength of contraction, can
adjust the length of the intrafusal fibres and thereby the responsiveness
of spindle sensory endings. In summary, the organization of spindles
allows them to monitor muscle conditions actively in order to compare
intended and actual movements, and to provide a detailed input to
spinal, cerebellar, extrapyramidal and cortical centres about the state of
the locomotor apparatus.
JOINT RECEPTORS
The arrays of receptors situated in and near articular capsules provide information on the position, movements and stresses acting on joints. fibres enclosed in a delicate capsule. The collagen bundles (intrafusal
fasciculi) are less compact than elsewhere in the tendon, the collagen
fibres are smaller and the fibroblasts larger and more numerous. A
single, thickly myelinated 1b afferent nerve fibre enters the capsule and
divides. Its branches, which may lose their ensheathing Schwann cells,
terminate in leaf-like enlargements containing vesicles and mitochon -
dria, which wrap around the tendon. A basal lamina or process of Schwann cell cytoplasm separates the nerve terminals from the collagen
bundles that constitute the tendon. Golgi tendon organs are activated
by passive stretch of the tendon but are much more sensitive to active
contraction of the muscle. They are important in providing propriocep -
tive information that complements the information coming from neu-romuscular spindles. Their responses are slowly adapting and they
signal maintained tension.
Neuromuscular spindles
Neuromuscular spindles are mechanosensors essential for propriocep -
tion (Boyd 1985). Each spindle contains a few small, specialized
intrafusal muscle fibres, innervated by both sensory and motor nerve
fibres (Figs 3.31–3.32). The whole is surrounded equatorially by a
fusiform spindle capsule of connective tissue, consisting of an outer
perineurium-like sheath of flattened fibroblasts and collagen, and an
inner sheath that forms delicate tubes around individual intrafusal
fibres (Fig. 3.33). A gelatinous fluid rich in glycosaminoglycans fills the
space between the two sheaths.
There are usually 5–14 intrafusal fibres (the number varies between
muscles) and two major types of fibre, nuclear bag and nuclear chain
fibres, which are distinguished by the arrangement of nuclei in their
sarcoplasm. In nuclear bag fibres, an equatorial cluster of nuclei makes
the fibre bulge slightly, whereas the nuclei in nuclear chain fibres form
a single axial row. Nuclear bag fibres are subdivided into bag1 and bag2
fibres, are greater in diameter than chain fibres and extend beyond the
surrounding capsule to the endomysium of nearby extrafusal muscle
fibres. Nuclear chain fibres are attached at their poles to the capsule or
to the sheaths of nuclear bag fibres.
The intrafusal fibres resemble typical skeletal muscle fibres, except
that the zone of myofibrils is thin around the nuclei. Dynamic bag1
fibres generally lack M lines, possess little sarcoplasmic reticulum, and
have an abundance of mitochondria and oxidative enzymes, but little
glycogen. Static bag2 fibres have distinct M lines and abundant glyco -
gen. Nuclear chain fibres have marked M lines, sarcoplasmic reticulum and T-tubules, and abundant glycogen, but few mitochondria. Each
fibre type carries distinct myosin heavy chain isoforms. These variations
reflect the contractile properties of different intrafusal fibres.
Muscle spindles receive two types of sensory innervation via the
unmyelinated terminations of large myelinated axons. Primary (anulo -
spiral) endings are equatorially placed and form spirals around the nucleated parts of intrafusal fibres. They are the endings of large sensory
fibres (group Ia afferents), each of which sends branches to a number
of intrafusal muscle fibres. Each terminal lies in a deep sarcolemmal
groove in the spindle plasma membrane beneath its basal lamina.
Secondary (flower spray) endings, which may be spray-shaped or anular,
are largely confined to bag2 and nuclear chain fibres, and are the
branched terminals of somewhat thinner myelinated (group II) affer -
ents. They are varicose and spread in a narrow band on both sides of the primary endings. They lie close to the sarcolemma, though not in
grooves. In essence, primary endings are rapidly adapting, while second -
ary endings have a regular, slowly adapting response to static stretch.
There are three types of motor endings in muscle spindles. Two are
from fine, myelinated, fusimotor ( γ) efferents and one is from myeli -
nated (β) efferent collaterals of axons that supply extrafusal slow twitch
muscle fibres. The fusimotor efferents terminate nearer the equatorial
region, where their terminals either resemble the motor end-plates of
extrafusal fibres (plate endings) or are more diffuse (trail endings).
Stimulation of the fusimotor and β-efferents causes contraction of the
intrafusal fibres and, consequently, activation of their sensory endings.
Muscle spindles signal the length of extrafusal muscle both at rest
and throughout contraction and relaxation, the velocity of their con -
traction and changes in velocity. These modalities may be related to the
different behaviours of the three major types of intrafusal fibre and their
sensory terminals. The sensory fusimotor endings of one type of nuclear bag fibre (dynamic bag1) are particularly concerned with signalling rapid changes in length that occur during movement, whilst those of the second bag fibre type (static bag2) and of chain fibres are less responsive to movement. These elements can therefore detect complex changes in the state of the extrafusal muscle surrounding spindles and can signal fluctuations in length, tension, velocity of length change and Fig. 3.31 A neuromuscular spindle, showing nuclear bag and nuclear
chain fibres within the spindle capsule (green); these are innervated by
the sensory anulospiral and ‘flower spray’ afferent fibre endings (blue) and
by the γ and β fusimotor (efferent fibre) endings (red). The β efferent fibres
are collaterals of fibres innervating extrafusal slow twitch muscle cells (M).
External capsule
Internal capsule
Nuclear bag fibre
Nuclear chain fibre
Subcapsular space
Primary (anulospiral)
ending of group 1a
afferent fibre
Secondary (flower
spray) ending ofgroup II afferent fibre
Trail ending ofγ-efferent fibre
Plate ending of
γ-efferent fibre
Plate ending ofM
β-efferent fibre | 110 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |
Neuromuscular junctions
63
CHAPTER 3
deeper layers and other articular structures (e.g. the fat pad of the tem -
poromandibular joint). They are rapidly adapting, low-threshold mech-
anoreceptors, sensitive to movement and pressure changes, and they
respond to joint movement and transient stresses in the joint capsule.
They are supplied by myelinated afferent axons but are probably not
involved in the conscious awareness of joint sensation.
Type III endings are identical to Golgi tendon organs in structure
and function; they occur in articular ligaments but not in joint capsules.
They are high-threshold, slowly adapting receptors and may serve, at
least in part, to prevent excessive stresses at joints by reflex inhibition
of the adjacent muscles. They are innervated by large myelinated affer -
ent axons.
Type IV endings are free terminals of myelinated and unmyelinated
axons that ramify in articular capsules and the adjacent fat pads, and around the blood vessels of the synovial layer. They are high-threshold,
slowly adapting receptors and are thought to respond to excessive
movements, providing a basis for articular pain.
NEUROMUSCULAR JUNCTIONS
SKELETAL MUSCLE
The most intensively studied effector endings are those that innervate muscle, particularly skeletal muscle. All neuromuscular (myoneural)
junctions are axon terminals of motor neurones. They are specialized
for the release of neurotransmitter on to the sarcolemma of skeletal
muscle fibres, causing a change in their electrical state that leads to
contraction. Each axon branches near its terminal to innervate from
several to hundreds of muscle fibres, the number depending on the
precision of motor control required (Shi et al 2012).
The detailed structure of a motor terminal varies with the type of
muscle innervated. Two major types of ending are recognized, innervat -
ing either extrafusal muscle fibres or the intrafusal fibres of neuromus -
cular spindles. In the former type, each axonal terminal usually ends midway along a muscle fibre in a discoidal motor end-plate ( Fig.
3.34A), and usually initiates action potentials that are rapidly con -
ducted to all parts of the muscle fibre. In the latter type, the axon gives
off numerous branches that form a cluster of small expansions extend -
ing along the muscle fibre; in the absence of propagated muscle excita -
tion, these excite the fibre at several points. Both types of ending are
associated with a specialized receptive region of the muscle fibre, the
sole plate, where a number of muscle cell nuclei are grouped within the
granular sarcoplasm.
The sole plate contains numerous mitochondria, endoplasmic retic -
ulum and Golgi complexes. The terminal branches of the axon are
plugged into shallow grooves in the surface of the sole plate (primary
clefts), from where numerous pleats extend for a short distance into the
underlying sarcoplasm (secondary clefts) ( Fig. 3.34B,C). The axon ter -
minal contains mitochondria and many clear, 60 nm spherical vesicles
similar to those in presynaptic boutons, which are clustered over the zone of membrane apposition. It is ensheathed by Schwann cells whose
cytoplasmic projections extend into the synaptic cleft. The plasma
membranes of the axon terminal and the muscle cell are separated by
a 30–50 nm gap and an interposed basal lamina, which follows the
surface folding of the sole-plate membrane into the secondary clefts. Endings of fast and slow twitch muscle fibres differ in detail: the sarco -
lemmal grooves are deeper, and the presynaptic vesicles more numer -
ous, in the fast fibres.
Junctions with skeletal muscle are cholinergic: the release of ACh
changes the ionic permeability of the muscle fibre (Sine 2012). Cluster -
ing of ACh receptors at the neuromuscular junction depends in part on the presence in the muscle basal lamina of agrin, which is secreted by
the motor neurone, and is important in establishing the postjunctional
molecular machinery. When the depolarization of the sarcolemma
reaches a particular threshold, it initiates an action potential in the
sarcolemma, which is then propagated rapidly over the whole cell
surface and also deep within the fibre via the invaginations (T-tubules)
of the sarcolemma, causing contraction. The amount of ACh released
by the arrival of a single nerve impulse is sufficient to trigger an action
potential. However, because ACh is very rapidly hydrolysed by the
enzyme AChE, present at the sarcolemmal surface of the sole plate, a single nerve impulse only gives rise to one muscle action potential, i.e. there is a one-to-one relationship between neuronal and muscle action potentials. Thus the contraction of a muscle fibre is controlled by the firing frequency of its motor neurone.
Neuromuscular junctions are partially blocked by high concentra -
tions of lactic acid, as in some types of muscle fatigue.Structural and functional studies have demonstrated at least four types
of joint receptor; their proportions and distribution vary with site. Three
are encapsulated endings, the fourth a free terminal arborization.
Type I endings are encapsulated corpuscles of the slowly adapting
mechanoreceptor type and resemble Ruffini endings. They lie in the
superficial layers of the fibrous capsules of joints in small clusters and
are innervated by myelinated afferent axons. Being slowly adapting,
they provide awareness of joint position and movement, and respond to patterns of stress in articular capsules. They are particularly common in joints where static positional sense is necessary for the control of posture (e.g. hip, knee).
Type II endings are lamellated receptors and resemble small versions
of the large Pacinian corpuscles found in general connective tissue. They occur in small groups throughout joint capsules, particularly in the Fig. 3.32 Nuclear bag and nuclear chain fibres in a neuromuscular
spindle. Dynamic β- and γ-efferents innervate dynamic bag1 intrafusal
fibres, whereas static β- and γ-efferents innervate static bag2 and nuclear
chain intrafusal fibres. Dynamic γ-efferent
Static γ-efferent
Afferent fibres
Static γ-efferent
Static β-efferent
Dynamic β-efferentII
II
Ia
Collaterals to
extrafusal muscleDynamic bag1
fibreStatic bag2
fibre
Long-chain
fibre
Short-chain
fibres
Fig. 3.33 A neuromuscular spindle in transverse section in a human
extraocular muscle. The spindle capsule (C) encloses intrafusal fibres (IF)
of varying diameters. Typical muscle fibres (M) in transverse section are
shown above the spindle. Toluidine blue stained resin section.
C
CIFC
CMM
IF | 111 | Gray's Anatomy | temp.pdf | https://ia802802.us.archive.org/30/items/GraysAnatomy41E2015PDF/Grays%20Anatomy-41%20E%20%282015%29%20%5BPDF%5D.pdf | PyPDF2TextLoader |