In vertebrate embryos, neural crest cells disperse through interstitial spaces, encounter a variety of different environmental cues and subsequently express a remarkable diversity of cellular phenotypes including neurons, glia, gland cells, pigment cells and connective tissue. Failure of normal neural crest development in humans, results in numerous diseases or syndromes, including (a) hereditary dysplasias such as Familial Dysautonomia, Hirschprung's disease (aganglionic megacolon), and hereditary neuropathies (e.g. ALS; Shy-Drager syndrome); (b) hereditary metaplasias, such an von Recklinghausen's disease (Neurofibromatosis) (c) numerous neural crest-derived neoplasias, such as gliomas, neuroblastomas, and pheochromocytomas; and (d) congenital defects such as cleft lip/palate, and craniofacial defects associated with heart malformation, such as Pierre Robin syndrome. Clearly, a detailed understanding of the regulatory mechanisms of normal neural crest development in vertebrates embryos will help elucidate such disease processes in humans and animals. We propose to test the hypothesis that developmentally-restricted cells segregate in a precise sequence from the neural crest lineage, and as a result of these early segregation events, subsets of crest-derived cells among early migrating crest populations respond differentially to localized environmental cues. Specifically, we will test our predictions that: (1) neurogenic precursors are present in early migrating crest cell populations In vitro; (2) survival of neurogenic precursors normally depends on their timely encounter with specific growth factor activities; (3) disappearance of the putative neurogenic precursor subpopulation is due to developmentally-regulated cell death; and (4) the lack of neurogenesis by crest-derived calls on the dorsolateral migration path, in vivo, is due to the absence of a neurogenic precursor subpopulation. The results of the proposed experiments will provide important insights about how neural crest cell diversification is regulated during early development. We anticipate that they will reveal: (1) the identity of developmentally-restricted populations that exist in the premigratory crest; (2) the specific responses of such crest-derived subpopulations to developmental cues; and (3) the identity of specific growth factors that mediate the developmental response of these subpopulations.
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