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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
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Apaydin N, Bozkurt M, Loukas M et al 2009 The course of the inferior gluteal
nerve and surgical landmarks for its localization during posterior
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landmarks for resection of the amygdala during medial temporal lobe
surgery. Neurosurgery 66:974–7.
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the spinal accessory nerve: technical note with potential application in
patients with high cervical quadriplegia. Childs Nerv Syst 24:1341–4.
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the drainage site of the vein of Labbé: application to neurosurgical
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anterior thoracic spine: a cadaveric feasibility study. J Neurosurg Spine 13:346–50.
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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.
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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
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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-
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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
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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
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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 |
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