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 and neuropathies such as Familial Dysautonomia and Hirschprung's disease (aganglionic megacolon), (b) hereditary metaplasias, such as von Recklinghausen's disease (Neurofibromatosis); (c) numerous neural crest-derived neoplasias, such as melanomas, Schwannomas, 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 among early migrating crest populations encounter specific, localized environmental cues on their migration pathways. (1) We will use immunocytochemical procedures, in combination with selective removal of matrix components, to detect specific growth factor immunoreactivities localized on crest cell migratory pathways in situ. Then, (2) we will characterize the distribution of extracellular matrix and growth factor immunoreactivity surrounding premigratory neural crest cells in vitro and in vivo. (3) To establish the normal role of such growth factors, we will compare the distribution of growth factor activity in the interstitial spaces of normal and mutant mouse embryos in which neural crest development is perturbed. Finally, (4) we will characterize the differentiation of crest cells on normal and mutant extracellular matrix substrata in the presence and absence of exogenous growth factors whose distribution in interstitial spaces had been altered by mutation. 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) what developmental signals are encountered by crest cells during their dispersal through embryonic interstitial spaces; (2) how relevant developmental cues are presented to responsive cells; and ultimately, (3) what molecular mechanisms mediate the responses of specific crest-derived subpopulations to these signals.
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