Wild sheep and many primitive domesticated breeds have two coats: coarse hairs covering shorter, finer fibres. Both are shed annually. Exploitation of wool for apparel in the Bronze Age encouraged breeding for denser fleeces and continuously growing white fibres. The Merino is regarded as the culmination of this process. Archaeological discoveries, ancient images and parchment records portray this as an evolutionary progression, spanning millennia. However, examination of the fleeces from feral, two-coated and woolled sheep has revealed a ready facility of the follicle population to change from shedding to continuous growth and to revert from domesticated to primitive states. Modifications to coat structure, colour and composition have occurred in timeframes and to sheep population sizes that exclude the likelihood of variations arising from mutations and natural selection. The features are characteristic of the domestication phenotype: an assemblage of developmental, physiological, skeletal and hormonal modifications common to a wide variety of species under human control. The phenotypic similarities appeared to result from an accumulation of cryptic genetic changes early during vertebrate evolution. Because they did not affect fitness in the wild, the mutations were protected from adverse selection, becoming apparent only after exposure to a domestic environment. The neural crest, a transient embryonic cell population unique to vertebrates, has been implicated in the manifestations of the domesticated phenotype. This hypothesis is discussed with reference to the development of the wool follicle population and the particular roles of Notch pathway genes, culminating in the specific cell interactions that typify follicle initiation.

We examined the number of elastic lamellae in the wall of the proximal aortic arch, aortic isthmus and descending aorta in patients with coarctation of the aorta. In the proximal aortic arch, the number of elastic lamellae was significantly lower in patients with coarctation compared to those with normal hearts without aortic anomalies and those with intracardiac defects but without aortic anomalies. The isthmus also showed a significantly lower number of elastic lamellae in the presence of preductal coarctation. In the descending aorta, the number of elastic lamellae was not significantly different between the different groups. There is doubt about the etiology of coarctation. Recent investigations showed that cells from the cardiac neural crest contribute to the formation of the arch arteries and the media of the arch. A developmental error of the neural crest might be responsible for the abnormal mural structures found in patients with aortic coarctation.

Both neurons and glia of the PNS are derived from the neural crest. In this study, we have examined the potential function of lunatic fringe in neural tube and trunk neural crest development by gain-of-function analysis during early stages of nervous system formation. Normally lunatic fringe is expressed in three broad bands within the neural tube, and is most prominent in the dorsal neural tube containing neural crest precursors. Using retrovirally-mediated gene transfer, we find that excess lunatic fringe in the neural tube increases the numbers of neural crest cells in the migratory stream via an apparent increase in cell proliferation. In addition, lunatic fringe augments the numbers of neurons and upregulates Delta-1 expression. The results indicate that, by modulating Notch/Delta signaling, lunatic fringe not only increases cell division of neural crest precursors, but also increases the numbers of neurons in the trunk neural crest.

In my Mannheimer lecture, designed to meet the needs of a mainly clinical audience, I present aspects of cardiac development that link basic science to clinically relevant problems. During development of the cardiac tube, and its subsequent changes as a dextrally looped structure, which is still connected to the dorsal body wall by a venous and an arterial pole, there are basic requirements. These consist of the development of myocardium, endocardium and the interposed cardiac jelly from the cardiogenic plates. In this primitive heart tube, septation and valvar formation then take place to convert it into a four-chambered heart. I demonstrate that the refining of the above events cannot take place without the addition of extracardiac populations of cells. These are presented as the “quintessence of heart development”, and consist of cells derived from the neural crest, along with epicardially derived cells. Without these contributions, the embryos uniformly die of cardiac insufficiency. Important contributions are made by the cells derived from the neural crest to septation and the formation of the arterial valves, and possibly in differentiation of the central conduction system. The epicardially derived cells are essential for formation of the interstitial fibroblasts and the myocardium, as well as the coronary vascular system. I conclude by discussing specific malformations of the heart that might be linked to these extracardiac contributions.

Cranial neural crest cells differentiate into diverse derivatives including neurons and glia of the cranial ganglia, and cartilage and bone of the facial skeleton. Here, we explore the function of a novel transcription factor of the spalt family that might be involved in early cell-lineage decisions of the avian neural crest. The chicken spalt4 gene (csal4) is expressed in the neural tube, migrating neural crest, branchial arches and, transiently, in the cranial ectoderm. Later, it is expressed in the mesectodermal, but not neuronal or glial, derivatives of midbrain and hindbrain neural crest. After over-expression by electroporation into the cranial neural tube and neural crest, we observed a marked redistribution of electroporated neural crest cells in the vicinity of the trigeminal ganglion. In control-electroporated embryos, numerous, labeled neural crest cells (∼80% of the population) entered the ganglion, many of which differentiated into neurons. By contrast, few (∼30% of the population) spalt-electroporated neural crest cells entered the trigeminal ganglion. Instead, they localized in the mesenchyme around the ganglionic periphery or continued further ventrally to the branchial arches. Interestingly, little or no expression of differentiation markers for neurons or other cell types was observed in spalt-electroporated neural crest cells.

Here we present ideas connecting the behaviour of the cranial neural crest during development with the venerable, perhaps incorrect, view that gill-supporting cartilages of an ancient agnathan evolved into the skeleton of an early gnathostome's jaw. We discuss the pattern of migration of the cranial neural crest ectomesenchyme in zebrafish, along with the subsequent arrangement of postmigratory crest and head mesoderm in the nascent pharyngeal segments (branchiomeres), in diverse gnathostomes and in lampreys. These characteristics provide for a plausible von Baerian explanation for the problematic inside-outside change in topology of the gills and their supports between these 2 major groups of vertebrates. We consider it likely that the jaw supports did indeed arise from branchiomeric cartilages.

The pectoral girdle articulates the forelimb with the axial skeleton in all vertebrates with paired anterior appendages. The structure of the pectoral girdle and its position along the axial skeleton has changed significantly during vertebrate evolution. These morphological changes have been well described, but there is little comparative embryology to indicate how these changes may have occurred. It is equally obscure how the muscles that connect the head with the pectoral girdle have maintained appropriate attachments even though these 2 structures have become separated. Here I review the changes in the pectoral girdle across different vertebrate taxa, indicating, where known, the developmental mechanisms underlying these changes. I also suggest how the muscular connections between the head and pectoral girdle have been maintained between these once adjacent bones, displaced during vertebrate evolution.

This review describes the evolutionary history of the mammalian skull vault as a basis for understanding its complex structure. Current information on the developmental tissue origins of the skull vault bones (mesoderm and neural crest) is assessed for mammals and other tetrapods. This information is discussed in the context of evolutionary changes in the proportions of the skull vault bones at the sarcopterygian-tetrapod transition. The dual tissue origin of the skull vault is considered in relation to the molecular mechanisms underlying osteogenic cell proliferation and differentiation in the sutural growth centres and in the proportionate contributions of different sutures to skull growth.

A muscularised pharynx, with skeletal support, serving the dual functions of feeding and respiration, is a fundamental vertebrate characteristic. Embryologically, the pharyngeal apparatus has its origin in a series of bulges that form on the lateral surface of the embryonic head, the pharyngeal arches, whose development is complex. These structures are composed of a number of disparate embryonic cell types: ectoderm, endoderm, neural crest and mesoderm, whose development must be coordinated to generate the functional adult apparatus. In the past, most studies have emphasised the role played by the neural crest, which generates the skeletal elements of the arches, in directing pharyngeal arch development, but it has also become apparent that the endoderm plays a prominent role in directing arch development. Neural crest cells are not required for arch formation, their regionalisation nor to some extent their sense of identity. Furthermore, the endoderm is the major site of expression of a number of important signalling molecules, and this tissue has been shown to be responsible for promoting the formation of particular components of the arches. Thus vertebrate pharyngeal morphogenesis can now be seen to be a more complex process than was previously believed, and must result from an integration of both neural crest and endodermal patterning mechanisms. Interestingly, this also mirrors the fact that the evolutionary origin of pharyngeal segmentation predates that of the neural crest, which is an exclusively vertebrate characteristic. As such, the evolution of the vertebrate pharynx is also likely to have resulted from an integration between these 2 patterning systems. Alterations in the interplay between neural crest and endodermal patterning are also likely to be responsible for the evolutionary that occurred to the pharyngeal region during subsequent vertebrate evolution.

Analysis of early development of the head of the Australian lungfish Neoceratodus forsteri indicates that no mesenchyme cells in this species enter the embryo as neurectoderm cells, originally positioned between presumptive ectoderm and primordial neural tissue of the embryo. Neural tissue in N. forsteri forms initially as a plate of columnar cells, flanked by raised folds of ectoderm, that sinks below the level of the ectoderm and forms a deep trough. Neural tissue separates from ectoderm, and fuses below the ectoderm to form a neural tube with cells arranged around a small central cavity. Subsequently, ectoderm unites to form a complete cover over the neural tissue. No migrating cells leave the ectodermal–neural junction during this process. No unsegmented column of cells appears dorsal to the neural tissue, before migration, as in teleosts and lampreys of equivalent stages. Neuromeres and tracts of cells leaving the central nervous tissues can be demonstrated in the developing neurula, but these are derived from neural tissue alone and appear after the formation of the neural keel is complete and neural structures have begun to develop. Mesenchyme cells are already present in large numbers, and are apparently derived from enterotomy or enter the embryo by involution at the blastopore. This finding explains previous experimental results in embryos of N. forsteri, which demonstrated that removal of cells from the margin of the neural folds, where higher vertebrate neural crest cells appear, apparently has little influence on the development of pigment cells or of skeletal and dental structures of the head.

Careful histological observation of the development of the anlage of the inner ear in chicken embryos led us to question the traditional view of otic placode (OP) formation. First, morphological studies in the cephalic region carried out on stages preceding the appearance of the placodal epithelium revealed that the medial placodal cells are continuous temporally and spatially with cells belonging to the neural fold (NF). Second, both the formation of the basal lamina between the dorsal region of the neural tube (NT) and ectoderm and the pattern of formation of the neural crest present distinctive characteristics between otic levels and regions located anteriorly and posteriorly. Third, numerical comparisons of parameters for the NT and the OP between different levels of the rhombencephalon allowed us to assign a differential behaviour in the growth pattern of the otic region. These results indicated that the medial part of the OP is not derived from already independent ectoderm that increases in thickness under the influence of the NT (as previously accepted) but that it develops directly from the NFs. Although we do not exclude other possibilities, we propose that at least a proportion of the OP cells originate directly from cells committed to be neural crest. After this incorporation, basal laminal formation would delimit the NT from the OP without transition of the otic cells to ectoderm. This hypothesis would imply that part of the otic cells originate directly from neuroepithelial cells having a neuroectodermal (rather than the previously established ectodermal) origin.

Development of the neural crest involves a remarkable feat of coordinated cell migration in which cells detach from the neural tube, take varying routes of migration through the embryonic tissues and then differentiate at the end of their journey to participate in the formation of a number of organ systems. In general, neural crest cells appear to migrate without the guidance of long-range physical or chemical cues, but rather they respond to heterogeneity in the extracellular matrix that forms their migration substrate. Molecules such as fibronectin and laminin act as permissive substrate components, encouraging neural crest cell attachment and spreading, whereas chondroitin sulphate proteoglycans are nonpermissive for migration. A balance between permissive and nonpermissive substrate components seems to be necessary to ensure successful migration, as indicated by a number of studies in mouse mutant systems where nonpermissive molecules are over-expressed, leading to inhibition of neural crest migration. The neural crest expresses cell surface receptors that permit interaction with the extracellular matrix and may also modify the matrix by secretion of proteases. Thus the principles that govern the complex migration of neural crest cells are beginning to emerge.

The cellular events leading to the generation of Schwann cells from the neural crest have recently been clarified and it is now possible to outline a relatively simple model of the Schwann cell lineage in the rat and mouse. Neural crest cells have to undergo 3 main developmental transitions to become mature Schwann cells. These are the formation of Schwann cell precursors from crest cells, the formation of immature Schwann cells from precursors and, lastly, the postnatal and reversible generation of non-myelin- and myelin-forming Schwann cells. Axonal signals involving neuregulins are important regulators of these events, in particular of the survival, proliferation and differentiation of Schwann cell precursors.

The melanotic neuro-ectodermal tumour of infancy is an uncommon benign tumour of neural crest origin occurring in infants with a predilection for the anterior maxilla. This lesion shows a good response to conservative surgical excision with few recurrences but it should be followed up for long periods of time because of the rare malignant change possible in the tumour.