View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Magazine R381 Primer specification of the neural crest. between the neural crest cells and More specifically, this inductive their neighbours within the dorsal event is mediated by members of neural tube. More specifically, it the Bmp family of signalling has been found that the The neural crest molecules. Both Bmp-4 and Bmp- delamination of neural crest cells 7 are expressed by the epidermal requires a switch in the repertoire Anthony Graham ectoderm, and the factors they of cell adhesion molecules encode will elicit the production of expressed by these cells. Thus, The neural crest is a transient and neural crest cells from the neural the crest cells down-regulate N- discrete embryonic cell population plate tissue. Furthermore, it has CAM and N-cadherin, which are of profound importance to the been recently suggested that generally expressed by cells of the development and the evolution of another signalling molecule, Wnt- neural tube. They also lose the the vertebrates. This cell type 6, which is also made in the expression of cadherin-6b, which emerges from the dorsal neural epidermal ectoderm, may also be is expressed more specifically tube during early development. involved in neural crest induction. within the neural tube by the cells Subsequently, the cells migrate It should also be noted, of the dorsalmost region. The into the periphery along however, that the interaction crest cells themselves then stereotypical paths to a number of between the neural plate and the upregulate cadherin-7. sites at which these cells stop and epidermal ectoderm does not just Interestingly, this delamination differentiate into a wide variety of induce the formation of the crest process is also controlled by derivatives. These include sensory but that it also induces other Bmps, most prominently Bmp-4, neurons, autonomic neurons, glia, dorsal neural tube cell types. This which comes to be expressed at melanocytes, cells of the adrenal is in keeping with the fact that the the dorsal midline of the neural medulla and, additionally in the neural folds do not exclusively tube. If Bmp-4 function is head, bone, cartilage, connective give rise to neural crest cells but perturbed, the neural crest cells tissue and smooth muscle cells. also to the other most dorsal cell cannot escape the neural tube and, Importantly, the neural crest is a types of the neural tube. Thus, in instead, accumulate within it. At unique feature of vertebrate essence, the interaction between least in part, Bmp-4 drives embryos, and the adult structures the neural plate and the epidermal delamination through up-regulation generated from the neural crest ectoderm does not directly induce of rhoB, which encodes a small are, fundamentally, those that the formation of the neural crest, GTP-binding protein and is distinguish the vertebrates from but rather results in the induction expressed specifically in the neural their nearest relatives. of the neural folds, which in turn crest cells prior to, and just after, Consequently, it has been give rise to neural crest, as well as delamination. If RhoB function is proposed that the evolution of the other very dorsal cell types. inhibited, the ability of the neural neural crest was key to the A consequence of this inductive crest to escape from the neural evolution of the vertebrates interaction is to stimulate the primordium is severely curtailed. themselves. expression of a number of transcription factors in the neural The migration of the neural crest The formation of the neural crest folds, which help mediate the In the trunk Induction generation of the neural crest. Once the neural crest cells escape In the embryo, the neural crest These have been found to include from the neural tube, they migrate cells first become manifest as they Pax gene products, members of along stereotypical pathways detach and leave the dorsal neural the Zic family, Slug and Foxd3. towards their sites of tube. However, the event that However, of these only Slug, a differentiation, and it would seem triggers the formation of the zinc finger transcription factor, that the pathway choices are neural crest occurs earlier in and FoxD3, a winged-helix dictated to the crest cells by development, during the process transcription factor, are environmental cues. The first of neurulation (Figure 1). A exclusively made in the neural structures encountered by crest consequence of this process, crest; the others are also made in cells as they leave the neural tube which involves the folding of the other cells within the dorsal neural are the somites, and, interestingly, flat neural plate into the neural tube. It is therefore likely that it is the migratory crest cells display a tube, is that the dorsal midline of Slug and FoxD3 which help define precise relationship with the the neural tube forms from the particular cells within the dorsal compartments of the somites. The edges of the neural plate that abut neural tube as being crest cells. early, ventrally migrating neural the epidermal ectoderm — the crest cells move through the neural folds. Thus, the neural crest Delamination sclerotome, the region of the is lineally derived from these Once the neural crest cells have somite that forms the axial structures. That the neural folds been induced, they have to leave skeleton, but, importantly, only form between the neural plate and the neural tube, and to do this through the anterior half the epidermal ectoderm betrays they must undergo a transition sclerotome of each somite (Figure the fact that it is an inductive from epithelial to mesenchymal 2). Neural crest cells do not enter interaction between these two type. Clearly this entails radical the posterior sclerotome of the tissues which underlies the alterations in the relationship somites. Of the ventrally migrating Current Biology Vol 13 No 10 R382 somites. Here, the early migratory ABC cells move ventrolaterally and populate the pharyngeal arches and facial prominences, Neural generating ectomesenchymal crest Neural Neural derivatives: bone, cartilage and folds plate connective tissue. The late migrating neural crest cells stay Notochord closer to the neural tube and Current Biology generate neurons and glia of the cranial ganglia. These crest cells, Figure 1. The induction of the neural crest occurs during the process of neurulation. however, do not migrate as a During neurulation, the neural plate (light blue) progressively folds to form the neural single mass, but are organised tube (A through to C). The ventral midline of the neural plate attaches to the notochord into three streams: trigeminal, (red). The neural folds (yellow) form at the interface between the neural plate and the epidermal ectoderm (dark blue), and the interaction between these two tissues is hyoid and post-otic. The required for the induction of the neural crest. The neural folds progressively come trigeminal neural crest arises from together to form the dorsal aspect of the neural tube and the neural crest (yellow). the midbrain and anterior hindbrain and forms neurons of cells, those that move furthest Ephrin-B1 and Ephrin-B2, and the trigeminal ganglion and the stop in the vicinity of the dorsal Sema-3A, while the crest cells components of the orofacial aorta and generate the neurons make the corresponding receptors, prominences and mandibular and glia of the sympathetic Eph-B2 and Eph-B3, and arch. The second stream, the ganglia. The remaining ventrally Neuropilin-1. Furthermore, in vitro hyoid, arises primarily from the migrating cells arrest more studies demonstrated that when central region of the hindbrain and dorsally within the anterior migrating neural crest cells are forms neurons of the proximal sclerotome, close to the neural confronted with a choice between facial ganglion as well as the tube and generate the sensory a permissive substrate, such as constituents of the second neurons and glia of the dorsal root fibronectin or Ephrin-B1, they pharyngeal arch. Finally, the post- ganglia (Figure 2). In contrast, the invariably avoid the ephrin domain otic crest is generated by the late migrating neural crest cells do and migrate along the fibronectin posterior hindbrain and forms the not follow this path, but migrate area, and, similarly, they will avoid neurons of the proximal and dorsolaterally between the a Sema-3A substrate. jugular ganglia, and the dermamyotomal region of the The somites are also involved in components of the posterior somite, which gives rise to muscle controlling the emigration of pharyngeal arches. and dermis, and the overlying neural crest cells along the This segregation of the neural ectoderm. These cells give rise to dorsolateral path. During the early crest into streams is important, as melanocytes (Figure 2). phases of crest migration, the it is required for normal A consequence of the migration dermamyotome and the ectoderm oropharyngeal development and of the early neural crest cells are in close contact, and the can have drastic consequences if it through only the anterior half dermamyotome actively inhibits is experimentally altered. The sclerotome of each somite is the migration. However, as the segregation of the head neural segmental organisation of their dermamyotome matures, it moves crest is evident as soon as the neuronal derivatives, the away from the somites and crest cells are born, and it is events sympathetic and the dorsal root cells do now enter the within the developing brain that are ganglia. In fact, the motor neurons dorsolateral path. The early responsible for establishing this that exit the spinal cord also only inhibitory role of the segregation. Studies in chick have enter the anterior sclerotome of dermamyotome is again mediated shown that one process that helps each somite and, thus, are also through production of Ephrin-B to enforce the segregation of the segmentally organised.