This article is based on my talk at the meeting "3rd Advances in Craniosynostosis: Basic Science to Clinical Practice", held at University College, London, on 25 August 2023. It describes my contribution, together with that of my research team and external collaborators, to the field of craniofacial development. This began with my PhD research on the effects of excess vitamin A in rat embryos, which led to a study of normal as well as abnormal formation of the cranial neural tube. Many techniques for analysing morphogenetic change became available to me over the years: whole embryo culture, scanning and transmission electron microscopy, cell division analysis, immunohistochemistry and biochemical analysis of the extracellular matrix. The molecular revolution of the 1980s, and key collaborations with international research teams, enabled functional interpretation of some of the earlier morphological observations and required a change of experimental species to the mouse. Interactions between the molecular and experimental analysis of craniofacial morphogenesis in my laboratory with specialists in molecular genetics and clinicians brought my research journey near to my original aim: to contribute to a better understanding of the causes of human congenital anomalies.

Throughout his long career, Ronan O'Rahilly contributed to many areas of Anatomy, but it is his outstanding contribution to human embryology that forms his major legacy. This interest was already evident in the first paper he published in the Journal of Anatomy (1946), in which he described a case of radial hemimelia in the right hand of a cook. In addition to presenting the abnormality anatomically, he discussed its possible developmental origins. Hence although his directly embryological work came later, it is clear that his instinct to ask ‘how did it get like that?’ was fundamental to his intellectual approach from the outset, as was the realisation that natural abnormalities could provide clues to normal development. His work was always absolutely meticulous, as was the manner in which his observations were reported. Ronan was born in Cork in 1921. His father, Dr Alfred O'Rahilly, was at that time Registrar, and later President, of University College, Cork. After qualifying in medicine at UCC in 1943, Ronan held clinical appointments for 3 years at the Royal Hospital, Sheffield. In 1944, he was sponsored for membership of the Anatomical Society by Professor Francis Davies. He continued his anatomical studies under the guidance of Professor M. A. MacConaill, who had moved from Sheffield to become head of anatomy at UCC in 1942. MacConaill's influence played a crucial part in Ronan's choice of profession. In a memoir he wrote a few years ago about his involvement with the Anatomical Society, Ronan mentioned several of the then current and former heads of department who influenced him and whose acquaintance he felt honoured to make during his attendance at the Society's meetings in his early years of membership. They included Alexander Low, James Couper Brash, Frank Goldby, Frederick Wood Jones, Sir Wilfred Le Gros Clark, Robert Lockhart and A. J. E. Cave. This reads like a list of famous anatomists of the mid-20th century; five of them were Presidents of the Anatomical Society. After completing his MSc in 1946, Ronan was appointed to an anatomy lectureship at the Durham University medical school at Newcastle upon Tyne. In 1948, he returned to Sheffield as a lecturer. In 1950, he took up a professorial appointment at Wayne State University, Detroit, followed by 7 years at St. Louis University, Missouri (1962–1969). Apart from three co-authored papers on the chick eye, all Ronan's output during this period concerned normal and abnormal human skeletal anatomy and development. His life was transformed in 1969 with his appointment to the prestigious post of Director of the Carnegie Institution's Embryological Collection, which he held at the same time as a second period at Detroit. Although very little of his published work had been purely developmental in subject matter up to this date, this appointment was clearly the catalyst that transformed Ronan from being a human anatomist to a human embryologist. Ronan launched himself into this new role with enthusiasm and seriousness, starting almost at the beginning of development with a study on the establishment of the embryonic axes. As his studies of the Carnegie embryos progressed, he became increasingly dissatisfied with the accepted definitions of developmental timing, which were at that time based on George L. Streeter's ‘Developmental Horizon's in Human Embryos’ (1942–1957). His patient nature was ideally suited to making a precise analysis of the Carnegie collection to create a more accurate scheme of stages, based on developmental characteristics. He published his proposed ‘Carnegie stages’ in a 1979 paper ‘Early human development and the chief sources of information on staged human embryos’ in the European Journal of Obstetrics, Gynaecology and Reproductive Biology (1979), with the clear intention that it should be noted by clinicians as well as research scientists. The following year, in a paper on the development of the vertebral column published jointly with his wife Fabiola Müller and D. B. Meyer, he wrote that in order to permit valid comparisons, the Carnegie stage should be cited if possible, and that “the term ‘horizon’ is obsolete”. By 1987, further refinement of the criteria and a series of careful papers on successive developmental stages resulted in a book, ‘Developmental Stages in Human Embryos’, written jointly with his wife. It covers the first 8 weeks of development, stages 1 to 23. The book is dedicated to the memory of Wilhelm His, who initiated the study of human embryology, and to his protégé Franklin P. Mall, the founder of the Carnegie Collection. The O'Rahilly–Müller duo's second book, ‘Human Embryology & Teratology’, has a very helpful summary of some of the key events at each developmental stage, with simple drawings. This very comprehensive book was a major undertaking and very successful; first published in 1990, it ran to three editions, the last one published in 2001. His extensive contributions to the nomenclature are evident throughout Terminologia Embryologica. The Carnegie Collection was initially established at Baltimore but moved to Washington, D.C. in 1960. In 1973–1974 it moved again, to the University of California at Davis, and Ronan moved there, too. He remained at Davis until his retirement in 1990. He then returned to Europe and lived for the rest of his life in Fribourg, Switzerland, where he held an honorary university position for 10 years. Even after that, his analysis of the Carnegie collection continued. His special interest in the nervous system was shared by his wife; they published many papers together on this aspect of development, and also produced a third book, ‘The Embryonic Human Brain: an Atlas of Developmental Stages’ (2006). Their last paper, published in 2013, was entitled ‘The longitudinal growth of the neuromeres and the resulting brain in the human embryo’. Ronan was an accomplished linguist and many of his scholarly publications were in French. He was widely versed in music, the graphic arts and literature. He delivered numerous prestigious lectures, many reflecting the application of his studies to pressing clinical problems, including the impact of the environment on the developing human. The value of his contributions has been recognised in honorary doctorates from University of Montpellier and the National University of Ireland. Nowadays, almost all advances in human embryology are made using molecular techniques. Nevertheless, the matter of where the molecular events and interactions take place remains central to understanding their significance. The meticulousness and precision of the work of Ronan and Fabiola fundamentally underpins the importance of this structural framework. Indeed, it will become more and more valuable with the increasing need to refine the exact location of such events, both normal and abnormal.

Ray Guillery was a major figure in the field of neuroanatomy, particularly of the visual system. His ancestry, early life and role models during his undergraduate and graduate training all provided influences that strengthened his innate bias towards this research career. His approach was rooted in descriptive anatomy and was driven by a desire to define and describe the pathways underlying visual function. In his autobiography (1998) he defended this approach as follows: ‘The important roots of neuroscience in accurate descriptive accounts are often overlooked, and the joy of arriving at a reasonably accurate and lasting description of a structural relationship is not as widely appreciated as perhaps it should be’. More prosaically, he was fond of saying: ‘If you can't draw it, you don't understand it’. This strongly defined aspect of his character led to him choosing to take a BSc degree in Anatomy at University College, London, instead of continuing his medical training. Ray was born on 28 August 1929, in Greifswald, Pomerania, on the Baltic coast of Germany. His father was a pathologist who, while training at the Charité Hospital, Berlin, met and married a Russian Jewish refugee who was a histology technician there. His paternal grandfather was a medically qualified ophthalmologist who specialised in visual acuity. His paternal grandmother's uncle, Otto Deiters, was an eminent neuroscientist whose name lives on in the lateral vestibular ‘Deiter's’ nucleus; the name was also originally applied to dendrites (Deiter's processes). There were medical relations on his mother's side, too; however, his maternal grandfather, an apothecary in St Petersburg before the First World War, had been forbidden by Nazi policies to practise by the time Ray knew him, and used to take the young boy to the zoo and on nature walks. Ray's parents divorced when he was quite young. The combination of this and the political situation meant that his family became scattered among different relatives, so his childhood was very disrupted. He attended a Rudolf Steiner school in Berlin (1935–38), followed by brief periods in Switzerland and Holland. At the end of the summer term 1939, he and his sister went to stay with his godmother in North London, where they were also reunited with their mother. The two siblings were booked to return to Holland on 3 September, but the outbreak of war that very day left them stranded in England. Their mother was acting as au pair to a London family who then evacuated their children to Oxford, where Ray attended a ‘rather shabby’ preparatory school before moving to Sibford School, a Quaker boarding school in the Cotswolds (1940–46). He felt as an adult that his moral outlook had been influenced by the first and last of these schools. His holidays were largely spent in the North Oxford home of Professor Wilfred Le Gros Clark and his wife, where his sister was based. Le Gros Clark was at that time Dr Lee's Professor of Anatomy (see obituary by Weddell, 1972); Ray described him as ‘rather silent and distant’ but enjoyed cycling with him in the countryside at weekends, and was introduced to his laboratory, including the primates in the animal house. Through Ernst Chain, who had known Ray's godmother's family in Berlin, his mother was enabled to pick up her professional skills after the war and work as a pathology technician. Being keen for him to become a doctor, she prepared slides with serial sections of a guinea pig embryo for his Christmas present one year, to go with the microscope he also received. Two years at a grammar school, and much independent work, resulted in a scholarship to study medicine at University College, London. There he was taught by J. Z Young and Bernard Katz among others and quickly became convinced that he wanted to aim for a career in research rather than medicine. He was awarded a scholarship to do an intercalated BSc in Anatomy, a new course started 2 years earlier, with P. K. Thomas as the only pupil that year (see obituary by King, 2008). In addition to the regular course of lectures and tutorials, chiefly by J. Z. Young, there were ‘intercollegiate’ lectures from other anatomists. Several of these were people who made important contributions to both Journal of Anatomy and the Anatomical Society, e.g. Frank Goldby, W. J. Hamilton, J. D. Boyd and E. C. Amoroso. After completing his BSc in 1951, Ray stayed on at UCL as a PhD student with a 2-year scholarship, under J. Z. Young's supervision. This was his first foray into neuroscience: a quantitative study of the axons of the fornix, from the hippocampus to the mammillary bodies of the hypothalamus. At the suggestion of his sister, he visited Oxford to re-establish contact with Le Gros Clark. There he discovered to his horror that Daitz, one of Le Gros Clark's research associates (the other was Tom Powell), was also working on the fornix. Fortunately it was a complementary pathway, so Ray's research plans were not affected; on the contrary, after Daitz's sudden death, he continued to collaborate with Tom, and the two of them, later joined by Max Cowan, had many productive discussions and joint publications over the years, several of which were published in this Journal. Ray remained at UCL as Assistant Lecturer, then Lecturer. He built on his thesis work by using the then new Nauta staining technique to trace the fibres from the fornix to the anterior thalamus. Like many of us early on in our research careers, he discovered that he had a competitor: Nauta himself had carried out the same study and had already submitted it to the Journal of Comparative Neurology. Ray nevertheless submitted his own paper to the Journal of Anatomy, which had a shorter publication delay, and both papers appeared in 1956. More pathway-tracing work using the Nauta method followed, and a paper in the Journal of Anatomy on the hypothalamic connections published in 1957 became a citation classic. Soon after this, his desire to understand the fine structure of synapses under different conditions drew him into electron microscopy. This early research was largely carried out without collaborators; obviously this changed as his career progressed, and it is not possible to give due credit to all of them in the account that follows. A year's sabbatical leave at the University of Wisconsin at Madison (1960–61) was not as productive from the research point of view as he had hoped but had the great advantage of widening his horizons in terms of methods of critical thinking as well as new contacts. On returning to London he began to work with Peter Ralston, successfully applying the Nauta stain to electron microscopy preparations. Technical developments at that time included the introduction of aldehyde fixation, which provided improved ultrastructural definition compared with that following osmium tetroxide fixation alone. Promotion to a Readership at UCL in 1963 and several job offers led him to think seriously about the future, and the following year he moved back to Madison, where he remained until 1977. In Madison he enjoying teaching undergraduate courses in neuroanatomy, and found his research very productive and rewarding. Colleagues and visitors included Max Cowan, Semir Zeki and Peter Ralston. Work on the visual system led to an interesting discovery about the fibre pathways from the retina to the lateral geniculate nucleus in Siamese cats: in this species, and (he later discovered) in all albinos, many of the fibres take an uncrossed instead of a crossed path. This means that the retinal input to the lateral geniculate nucleus is abnormal, and the animals lack binocular vision. An offer from the University of Chicago enabled Ray to take up a challenge he had long desired, that of setting up a graduate neurobiology programme; he ran this successfully and with much enjoyment from 1977 to 1984. His work on the visual pathways continued and was extended to pigmented and albino ferrets: these have the advantage of being born at a less advanced stage of visual development than are cats, so can be studied postnatally at stages that are prenatal in cats. In 1984, Ray was appointed to the Dr Lee's Chair of Anatomy at Oxford. This chair was founded in 1919 with the appointment of Arthur Thomson, and held by Wilfred Le Gros Clark from 1934 to 1962. After the initial difficulties he inherited with the poor relations between academic and technical staff, things ran smoothly. He was very supportive of his research-active academic staff, one of whom was his old collaborator Tom Powell. He was also very keen to ensure that all the teaching was done to the highest standards and, not surprisingly, he took a very active interest in the neuroanatomy classes. Although he encouraged junior staff to take the lead, he was always there to demonstrate in the practical sessions, where his expertise was much sought after not only by the students but also by the staff. His research group was active and productive; in addition to his work on the optic chiasm, he investigated the thalamic reticular nucleus. This was the renewal of a project begun in Madison; it led to the discovery of an adjacent group of cells, the perireticular nucleus, whose functional significance is still not clearly understood. While at Oxford he became the founding Editor-in-Chief of the European Journal of Neuroscience, a position he greatly enjoyed. He served as President of the Anatomical Society from 1993 to 1995, was Treasurer of the Society for Neuroscience and was on the editorial board of several neuroscience journals. Retirement in 1996 did not bring Ray's research career to an end: he returned to Madison with the title of Visiting Professor and Senior Scientist, and continued active experimental work and publication there for another 10 years. In 1954, Ray married Margot Pepper, at that time a medical student at St Mary's; they had four children. Sadly, what had been a happy marriage for 30 years did not survive the move from Chicago in 1984, where she had a staff position in Dermatology. The promised position for her in Oxford did not materialise, and she returned to the USA. Their youngest child, Jane, married a Turk and works as a teacher and translator in Istanbul. Ray moved there from Wisconsin in 2006 as visiting professor in the Anatomy Department of Marmara University, to be closer to her and his grandchildren. By 2010, growing deafness and an inability to speak Turkish made him feel increasingly isolated, and he returned to Oxford, where he lived until his death. For most of those last years he was again a very welcome demonstrator in the neuroanatomy classes, and always enjoyed chatting about some of the latest neuroanatomical findings in the mid-session coffee break. He welcomed visitors to his compact house with its well-kept vegetable garden, where he gave G.M.-K. some very helpful information on the historical aspects of neuroanatomy for her articles on the history of the Journal of Anatomy. Ray's last paper (Dieters and Guillery, 2013), co-authored with his cousin, was a review of the work of their great-great uncle, the neuroscientist Otto Deiters (1834–63). This was a very appropriate way to tie together his family history and his neuroanatomical research, and a fitting end to a lifetime of scientific publication.

This chapter discusses the pathology of the spinal cord and the peripheral nervous system, which consists of cranial and spinal nerves, peripherally located sensory and autonomic ganglia, and nerve endings. There is an overview of the embryology of the spinal cord and peripheral nervous system, a description of the commonly encountered spontaneous lesions seen in Wistar, Sprague–Dawley, F344 and other rat strains seen in routine safety assessment studies (including carcinogenicity studies) and concludes with concise descriptions of classic examples of neurotoxic compounds that act on the spinal cord and peripheral nervous system.

The craniofacial region includes the cranium, face, and those structures of the ventral neck that are derived from the embryonic pharynx. It is characterized by a major contribution from the neural crest (NC), a tissue unique to vertebrate embryos. NC cells contribute the mesenchymal components of the face, much of the skull base and vault, the cranial ganglia, and the glands of the neck; they also form melanocytes. The mesoderm forms the skeletal and connective tissue components of the head caudal to the NC domain. Ectodermal placodes are unique to the head; they form the nasal epithelium, lens, and otocysts and contribute neuroblasts to the cranial ganglia. Two tissue boundaries are of major importance in craniofacial morphogenesis: the boundary between the ectoderm and the endoderm in the developing oral cavity, and the boundary between the mesodermal mesenchyme and the NC-derived mesenchyme. The ectoderm–endoderm boundary is at first formed by a physical barrier, the buccopharyngeal membrane. The Rathke's pouch, which forms the anterior pituitary gland, develops as a diverticulum on the ectodermal side of the membrane. The endodermal side is aligned with the rostral tip of the notochord and the boundary between the mesodermal mesenchyme and the NC-derived mesenchyme in the skull base. In the skull vault, the NC–mesoderm boundary forms the frontoparietal (coronal) suture. Up to E10.5 (TS 17), the NC–mesoderm boundary is co-aligned in the tissues that will form the skull, the dermis, and the meningeal covering of the brain, but as the cerebral hemispheres increase in size, this alignment is lost through differential growth. Craniofacial tissues whose development is not constrained by major boundaries include melanocytes, muscles, and the endothelium of blood vessels.

The Journal of Anatomy was launched 150 years ago as the Journal of Anatomy and Physiology , in an age when anatomy and physiology were not regarded as separate disciplines. European science in general was advancing rapidly at the time (it was 7 years after publication of Darwin's Origin of Species ), and the recent demise of the Natural History Review meant that there was no English language publication covering these subjects. The founding editors were George Murray Humphry of Cambridge and William Turner of Edinburgh, together with Alfred Newton of Cambridge and Edward Perceval Wright of Dublin (the last two served only for a year). The pivotal event leading to the Journal 's foundation was the 1866 meeting of the British Association, at which Humphry delivered the ‘Address in Physiology’ (printed in the first issue). Turner, who was also present at the 1866 British Association meeting, remained as a member of the editorial team for 50 years and was a major contributor of Journal articles. The title was changed to Journal of Anatomy in October 1916, when it was taken under the wing, in terms of both management and ownership, by the Anatomical Society . This article reviews the early years of the Journal’ s publication in more detail than later years because of the historical interest of this less familiar material. The subject matter, which has remained surprisingly consistent over the years, is illustrated by examples from some notable contributions. The evolution of illustration techniques is surveyed from 1866 to the present day; the final section provides brief summaries of all of the chief editors.

We are sad to report the early death of Matthew Kaufman, emeritus Professor of Anatomy at the University of Edinburgh and the leading mouse developmental anatomist of his generation. In a long and very productive research career, he wrote more than 200 papers and a dozen books on mouse development and on Scottish medical history. Matt grew up in a very orthodox and rather poor Jewish family in London. His parents saw him as a future scribe, writing the Torah (the five books of Moses) in Hebrew on parchment, but the only long-term effect of this was his exquisite handwriting. His own life choice was to study medicine at the University of Edinburgh, where after qualification he specialized in obstetrics. This led him to become interested in reproductive physiology and to work as a research associate with Professor Anne McLaren at her Edinburgh MRC research unit. Realising that he much preferred research to medical practice, he moved to the Marshall Laboratory in the Department of Physiology, University of Cambridge in 1970 to study for a PhD on mouse parthenogenesis under the supervision of Professor C. R. (Bunny) Austin. After this, he spent two years at the Weizmann Institute in Israel with Professor Leo Sachs, returning to Cambridge as a University Demonstrator then University Lecturer in anatomy. His early work was summarized in a monograph, Parthenogenetic Studies (1983, C.U.P). Matt's first major contribution to science was to collaborate with Martin Evans in the development of mouse embryonic stem (ES) cells – these were initially called Evans-Kaufman (EK) cells. The five papers they published together in 1981–4, together with those of Gail Martin in the USA at around the same time, provided the baseline knowledge for all subsequent work on the genetic manipulation of ES cells, their use in making transgenic mouse strains and their potential in regenerative medicine. Matt's contribution to this work was mainly the dissection of blastocysts to provide inner cell mass cells for culture, using the fine manipulative skills he had acquired during his parthenogenesis studies. Although he took no part in the exploitation of the technique for genetic manipulation, it was his knowledge of the use to which ES cells were being put that led to his recognition of the need for a resource of information on mouse developmental anatomy. It is the production of this resource for which he is now best known: his Atlas of Mouse Development, was a huge labour of love that took a decade to complete. For it, Matt analyzed, photographed and provided detailed labels and explanations for around 1500 micrographs of sections from all 26 Theiler stages of mouse embryos, together with diagrams and scanning electron micrographs of each stage. The sections of older stages include over 100 labels for each. The timing of its publication in 1992 was perfect, coinciding as it did with an explosion of studies on the developmental expression of newly cloned genes in mouse embryos, when molecular biologists new to embryology desperately needed an accessible source of information for the interpretation of new in situ hybridization patterns. By the standards of books on mouse development, this book has been and continues to be a bestseller (to the pleasant surprise of Academic Press, the publisher); a multi-author supplement that will be part of Matt's legacy is in preparation. It will include a set of coronal sections (few of which were included in the original book) that he prepared and partly labeled before his death. In addition to its originally intended function, the Atlas provided the anatomical infrastructure used to compile the informatics of mouse development currently in use for the formal storage of new data on normal and abnormal mouse genetics. Around the time of publication, mouse informatics was getting off the ground both at the Jackson Laboratory in Maine and at the MRC Human Genetics Unit in Edinburgh, and it was soon clear that more was needed than just the basic genomics. One of us (JBLB) approached Matt and suggested that, for each Theiler stage, we should integrate all of the tissues into a “parts-of” hierarchy. One benefit of this would be that his beloved Atlas would get a proper index; another of course would be that the hierarchy (which soon became an ontology) could be used as the anatomical core for a database to which could be added tissue-associated data (e.g. gene-expression). This was implemented by the Jackson Laboratory and is now a key feature of the mouse informatics resource there. The collaboration also resulted in a book with JBLB, The Anatomical Basis of Mouse Development, which links the Atlas to the development of the various organ systems. At the MRC Human Genetics Unit, Richard Baldock, Duncan Davidson and JBLB decided to go further and to make 3D reconstructions of mouse embryos from the slides that Matt had used for his Atlas and to include all the tissue boundaries so that gene expression could be shown accurately. This led Baldock and Davidson to produce the first online graphical atlas for capturing gene-expression data, to which Matt continued to provide detailed anatomical input until about 2011. In 1985, some years earlier, Matt had been appointed to the chair of anatomy at the University of Edinburgh, a post established in 1705; he remained there until his retirement in 2007. The University did not view his tenure of the chair as entirely successful for two reasons. First, they had hoped that he would introduce molecular biology into the department, but he was not really equipped to do this. Second, they wished to reduce the amount of anatomical teaching in the curriculum to make room for genetics and social medicine; this shocked Matt because he believed that all of medicine stemmed from anatomy and that the best way of teaching anatomy, as well as the rest of medicine, was from the cadaver. He therefore opposed the inevitable changes at every stage. In hindsight, he lost more battles than he need have done, probably because for all his academic strengths his personality did not equip him to be a successful university politician. The problems were exacerbated by ill health: in 1995 he developed polycythaemia, a myeloproliferative neoplasm resulting in the overproduction of red blood cells. He spent the rest of his life on the maximum dose of methotrexate that his body could tolerate, and lived in a state of continuous discomfort. This is not to say that he had stopped or, indeed, ever stopped his involvement in research and scholarship. He had a deep love of anatomy, both mouse and human, and served on the editorial board of Journal of Anatomy for many years as an advisor and referee for embryological research articles. His interest in the medical history (mainly of anatomy) of Scotland in general and the University of Edinburgh in particular led him to write a series of articles and books on medical history from 1992 onwards. The most important of these was a history of the Edinburgh chair of anatomy that was part of the exhibition he organized in 2005 to celebrate the 300th anniversary of its foundation. By this time he was approaching retirement and there was some degree of reconciliation between him and the University. Indeed, there was no argument when, in 2007, he was elected to the Royal Society of Edinburgh. Matt was fortunate in having a very happy home life. Claire, his wonderfully tolerant wife, put up with his never-ending work, his 1930s Lagonda car that was always breaking down and the sheer quantity of working papers, historical documents, research publications and histological slides that littered the house as well as his very large office in the university. Matt was a loving husband and father; Claire and their two sons are justly proud of him. We, his friends and former colleagues in Cambridge (GMMK) and Edinburgh (JBLB), join them in remembering with affection his somewhat eccentric interests, his kindness, his ability, his old-fashioned courtesy and his personal warmth.

C16orf35 is a conserved and widely expressed gene lying adjacent to the human α-globin cluster in all vertebrate species. In-depth sequence analysis shows that C16orf35 (now called NPRL3) is an orthologue of the yeast gene Npr3 (nitrogen permease regulator 3) and, furthermore, is a paralogue of its protein partner Npr2. The yeast Npr2/3 dimeric protein complex senses amino acid starvation and appropriately adjusts cell metabolism via the TOR pathway. Here we have analysed a mouse model in which expression of Nprl3 has been abolished using homologous recombination. The predominant effect on RNA expression appears to involve genes that regulate protein synthesis and cell cycle, consistent with perturbation of the mTOR pathway. Embryos homozygous for this mutation die towards the end of gestation with a range of cardiovascular defects, including outflow tract abnormalities and ventriculoseptal defects consistent with previous observations, showing that perturbation of the mTOR pathway may affect development of the myocardium. NPRL3 is a candidate gene for harbouring mutations in individuals with developmental abnormalities of the cardiovascular system.

The relationship between the visual arts and anatomy is rich and diverse, encompassing illustration of the body for anatomists and the study of anatomy by artists, while artistic creativity itself has a functional neuroanatomical basis. These aspects of the art-anatomy relationship are the subject of this special issue of Journal of Anatomy, which arose from presentations at a symposium sponsored by the Anatomical Society of Great Britain and Ireland, held in Oxford in January 2009. The creation of two- and three-dimensional artefacts requires both manual dexterity and the ability to ‘see with the mind’s eye’. The first three articles in this issue, which cover the evolutionary perspective and functional neuroanatomy/neuropsychology, approach the subject from this point of view. An article by one of us (GMM-K) sets the scene by considering what we can deduce from existing evidence about the evolution of human artistic creativity. We cannot know the processes of neuronal change that led to the evolution of a human brain with the capacity for artistic creativity and aesthetic appreciation, but both the history of tool making and ‘proto-art’ artefacts provide clues as to what the evolving brain was able to perceive and to direct the hands to construct. Dahlia Zaidel’s article develops this theme by providing a deeper analysis of current understanding of the evolutionary origins of the neuroanatomical basis of art and aesthetics. By describing neuroanatomical studies of brain-damaged artists, she also shows that artistic creativity is not located in a discrete region of the brain, but is a complex, dispersed and flexible neural function. Thomas Jacobsen extends this theme to neuroaesthetics, through a cognitive psychological approach to the concept of beauty. Through functional Magnetic Resonance Imaging data, he introduces studies on neural processing of the perception of beauty. Anatomical illustration is fundamentally important to the teaching and study of anatomy. Martin Kemp provides a comprehensive overview of the stylistic changes in the illustration of anatomical texts from the fifteenth century to the present day, with some fascinating insights into the relationship between anatomical art and the knowledge of anatomy inherent in the paintings of the Renaissance masters. The early anatomical illustrations also had a profound influence on the first wax modellers, as Alessandro Riva and colleagues show, with special reference to the paintings of Fabricius and others in the 16th and 17th centuries, and to the extraordinarily beautiful wax models made by Clemente Susini in the late 18th-early 19th centuries. Roberta Ballestriero provides further perspectives on anatomical waxes, showing the stark contrast between the style of the London-based Joseph Towne and that of the Florentine artists, and providing a historical perspective on the use of wax for votive and other artefacts from Roman times to the present day. The wax modellers were so accurate in their portrayals that one of Susini’s models of a young pregnant woman has reproduced a cardiovascular defect, presumably the cause of death, analysed here for the first time by Giovanni Mazzotti and colleagues. In her article on anatomical waxes, Roberta Ballestriero confronts the issue of whether these models should be regarded as art or craft. Caroline Wilkinson asks a similar question of her work on facial reconstruction, a process that requires a thorough knowledge of anatomy. However, a degree of artistic licence is appropriate and inevitable where unknowable components of the anatomy are involved, such as details of ears and skin colour. The unpredictable elements are fewer than one might imagine – skeletal detail guides the size of the ear lobes and the form of the soft part of the nose to a surprising extent. Since the Renaissance, artists have recognised the importance of anatomical knowledge for their own creative work (though this is less universally acknowledged today). The Romanian artist Constantin Brâncuşi, before creating the forms of characteristically simple beauty for which he is best known, studied anatomy and made at least two forms of full-sized écorché (skinned) figures. Andy Chirculescu and colleagues introduce us to these little-known works and their historical context in a short article. Karen Ingham brings us up to date with a working artist’s relationship to anatomy, viewing the relationship between the artist, the human body and the public as an ongoing dialogue. In her article she presents work by artists, including herself, that illuminates contemporary ideas of the body in life, death and disease within the appropriate architectural contexts. No volume on art and anatomy would be complete without an article that illustrates the use of computer graphics in modern medical imaging. John McGhee’s work creates three-dimensional computer-generated images from clinical scan data such as Magnetic Resonance Imaging. He uses the tools of the digital animator to create visually pleasing anatomical images that are accessible to the lay viewer, with the ultimate aim of creating a tool for communication between clinicians and their patients. We thank all of the contributors to this volume for the very high quality of their articles, to the reviewers who provided very constructive comments and were incredibly generous with their time, and the managing editor, Edward Fenton, for his patience and help, especially with authors not accustomed to the electronic submission system. Finally, we thank the Anatomical Society of Great Britain and Ireland for sponsoring the Art of Anatomy symposium, and the contributors, some of whom travelled long distances to give the stimulating talks on which these articles are based.

The central nervous system comprises the brain and spinal cord which provide sensation, control of movement, emotion, aesthetics, reason and self-awareness. The tissue that makes up the central nervous system is highly differentiated and exceedingly ordered, yet plastic. The central nervous system is well protected throughout by a fluid-filled, tri-layered, connective tissue covering (the meninges) and various osseous claddings. The cranium provides a rigid armor for the brain whereas the vertebral column constitutes the flexible protection of the spinal cord. Because the focus of this volume is the study of various disease states that affect the functions of the brain, it is important to understand the normal relationship of the brain to its surrounding structures including its bony case and its connective tissue coverings, its blood supply, and its internal organization, as well as how the perturbation of the relationships among these structures can impact brain functions. It is the purpose of this chapter to present an overview of this information. More detailed anatomical information is readily available in textbooks of gross anatomy and neuroscience.

Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mutation (equivalent to P244R) into the murine Fgfr3 gene. A rounded skull and shortened snout (often skewed) with dental malocclusion was observed in a minority of heterozygotes and many homozygotes. Development of this incompletely penetrant skull phenotype was dependent on genetic background and sex, with males more often affected. However, these cranial abnormalities were rarely attributable to craniosynostosis, which was only present in 2/364 mutants; more commonly, we found fusion of the premaxillary and/or zygomatic sutures. We also found decreased cortical thickness and bone mineral densities in long bones. We conclude that although both cranial and long bone development is variably affected by the murine Fgfr3 P244R mutation, coronal craniosynostosis is not reliably reproduced. Developmental Dynamics 238:331–342, 2009. © 2008 Wiley‐Liss, Inc.

Skull sutures serve as growth centers whose function involves multiple molecular pathways. During periods of brain growth the sutures remain thin and straight, later developing complex fractal interdigitations that provide interlocking strength. The nature of the relationship between the molecular interactions and suture pattern formation is not understood. Here we show that by classifying the molecules involved into two groups, stabilizing factors and substrate molecules, complex molecular networks can be modeled by a simple two-species reaction-diffusion model that recapitulates all the known behavior of suture pattern formation. This model reproduces the maintenance of thin sutural tissue at early stages, the later modification of the straight suture to form osseous interdigitations, and the formation of fractal structures. Predictions from the model are in good agreement with experimental observations, indicating that the model captures the essential nature of the interdigitation process.

The mouse mutant Doublefoot (Dbf) shows preaxial polydactyly with 6–9 triphalangeal digits in all four limbs and additional abnormalities including a broadened skull, hydrocephalus, and a thickened, kinked tail. The autopod undergoes a characteristic expansion between late embryonic day (E) 10.5 and E11.5, following the onset of ectopic Indian hedgehog (Ihh) expression in the entire distal mesenchyme, except for the zone of polarising activity (ZPA), at E10.5. We show here that limb prepattern, as indicated by expression of Gli3 and Hand2 at E9.5 is unaffected by the mutation. As both Sonic hedgehog (Shh) and Ihh expression are present in Dbf limb buds at E10.5, we generated Dbf/+;Shh−/− mutants to analyse the effects of different patterns of Hedgehog activity on the limb phenotype and molecular differentiation. Dbf/+ embryos lacking Shh showed postaxial as well as preaxial polydactyly, and the Ihh expression domain extended posteriorly into the domain in which Shh is normally expressed, indicating loss of ZPA identity. Differences in gene expression patterns in wild type, single and compound mutants were associated with differences in Gli3 processing: an increased ratio of Gli3 activator to Gli3 repressor was observed in the anterior half of Dbf/+ limb buds and in both anterior and posterior halves of compound mutant limb buds at E10.5. To identify the cause of Ihh misregulation in Dbf/+ mutants, we sequenced ∼20 kb of genomic DNA around Ihh but found no pathogenic changes. However, Southern blot analysis revealed a ∼600 kb deletion disrupting or deleting 25 transcripts, starting 50 kb 5′ of Ihh and extending away from the gene. The large deletion interval may explain the wide range of abnormalities in Dbf/+ mutants. However, we did not detect anologous deletions in cases of Laurin–Sandrow syndrome, a human disorder that shows phenotypic similarities to Dbf.

TGFb1 and TGFb3 are partially redundant effectors in brain vascular morphogenesis 508 Polydactyly in the mouse mutant Doublefoot involves altered Gli3 processing and is caused by a large deletion in cis to Indian hedgehog 517 Subtypes of glial cells in the Drosophila embryonic ventral nerve cord as related to lineage and gene expression 542

The vertebrate cranial base is a complex structure composed of bone, cartilage and other connective tissues underlying the brain; it is intimately connected with development of the face and cranial vault. Despite its central importance in craniofacial development, morphogenesis and tissue origins of the cranial base have not been studied in detail in the mouse, an important model organism. We describe here the location and time of appearance of the cartilages of the chondrocranium. We also examine the tissue origins of the mouse cranial base using a neural crest cell lineage cell marker, Wnt1-Cre/R26R, and a mesoderm lineage cell marker, Mesp1-Cre/R26R. The chondrocranium develops between E11 and E16 in the mouse, beginning with development of the caudal (occipital) chondrocranium, followed by chondrogenesis rostrally to form the nasal capsule, and finally fusion of these two parts via the midline central stem and the lateral struts of the vault cartilages. X-Gal staining of transgenic mice from E8.0 to 10 days post-natal showed that neural crest cells contribute to all of the cartilages that form the ethmoid, presphenoid, and basisphenoid bones with the exception of the hypochiasmatic cartilages. The basioccipital bone and non-squamous parts of the temporal bones are mesoderm derived. Therefore the prechordal head is mostly composed of neural crest-derived tissues, as predicted by the New Head Hypothesis. However, the anterior location of the mesoderm-derived hypochiasmatic cartilages, which are closely linked with the extra-ocular muscles, suggests that some tissues associated with the visual apparatus may have evolved independently of the rest of the "New Head".

This paper introduces a novel approach to quantify asymmetry in each point of a surface. The measure is based on analysing displacement vectors resulting from nonrigid image registration. A symmetric atlas, generated from control subjects is registered to a given subject image. A comparison of the resulting displacement vectors on the left and right side of the symmetry plane, gives a point-wise measure of asymmetry. The asymmetry measure was applied to the study of Crouzon syndrome using Micro CT scans of genetically modified mice. Crouzon syndrome is characterised by the premature fusion of cranial sutures, which gives rise to a highly asymmetric growth. Quantification and localisation of this asymmetry is of high value with respect to surgery planning and treatment evaluation. Using the proposed method, asymmetry was calculated in each point of the surface of Crouzon mice and wild-type mice (controls). Asymmetry appeared in similar regions for the two groups but the Crouzon mice were found significantly more asymmetric. The localisation ability of the method was in good agreement with ratings from a clinical expert. Validating the quantification ability is a less trivial task due to the lack of a gold standard. Nevertheless, a comparison with a different, but less accurate measure of asymmetry revealed good correlation.

Crouzon syndrome is a genetic disease resulting in premature fusion of cranial sutures and synchondroses causing craniosynostosis. A decade ago the Crouzon gene was discovered, and recently the first mouse model of the syndrome was generated. In this study, a set of micro CT scannings of the heads of wild-type (normal) mice and Crouzon mice were investigated. We present for what we believe is the first time, a statistical deformation model based on independent component analysis (ICA). A set of deformation parameters for each mouse was calculated using a B-spline-based non-rigid registration. From the parameters controlling the deformations for each subject, the statistical model was estimated. ICA is demonstrated to provide localized deformation components, many of which give a clear separation between Crouzon and wild-type mice. This is a clear improvement of a previous principal component-based model, which only provided one global deformation component describing the disease. The ICA components allow interpretation of each deformation feature to be carried out independently of other features, and provides a basis for linking the observed craniofacial malformations to the fusing of sutures. ICA revealed an interesting new finding, not previously reported in the literature, namely asymmetries in the head in Crouzon mice. This phenomenon is probably caused by asymmetric closure of craniofacial sutures

Crouzon syndrome is characterised by the premature fusion of cranial sutures. Recently the first genetic Crouzon mouse model was generated. In this study, Micro CT skull scannings of wild-type mice and Crouzon mice were investigated. Using nonrigid registration, a wild-type craniofacial mouse atlas was built. The atlas was registered to all mice providing parameters controlling the deformations for each subject. Our previous PCA-based statistical deformation model on these parameters revealed only one discriminating mode of variation. Aiming at distributing the discriminating variation over more modes we built a different model using Independent Component Analysis (ICA). Here, we focus on a third method, sparse PCA (SPCA), which aims at approximating the properties of a standard PCA while introducing sparse modes of variation. The results show that SPCA outperforms both ICA and PCA with respect to the Fisher discriminant, although many similarities are found with respect to ICA.