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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE004316-14A2
Application #
3219016
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1976-05-01
Project End
1994-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
14
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Oregon
Department
Type
Other Domestic Higher Education
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Weston, James A; Yoshida, Hisahiro; Robinson, Victoria et al. (2004) Neural crest and the origin of ectomesenchyme: neural fold heterogeneity suggests an alternative hypothesis. Dev Dyn 229:118-30
Wehrle-Haller, B; Meller, M; Weston, J A (2001) Analysis of melanocyte precursors in Nf1 mutants reveals that MGF/KIT signaling promotes directed cell migration independent of its function in cell survival. Dev Biol 232:471-83
Wehrle-Haller, B; Weston, J A (1999) Altered cell-surface targeting of stem cell factor causes loss of melanocyte precursors in Steel17H mutant mice. Dev Biol 210:71-86
Weston, J A (1998) Lineage commitment and fate of neural crest-derived neurogenic cells. Adv Pharmacol 42:887-91
Wehrle-Haller, B; Weston, J A (1997) Receptor tyrosine kinase-dependent neural crest migration in response to differentially localized growth factors. Bioessays 19:337-45
Wehrle-Haller, B; Morrison-Graham, K; Weston, J A (1996) Ectopic c-kit expression affects the fate of melanocyte precursors in Patch mutant embryos. Dev Biol 177:463-74
Wehrle-Haller, B; Weston, J A (1995) Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development 121:731-42
Morrison-Graham, K; Takahashi, Y (1993) Steel factor and c-kit receptor: from mutants to a growth factor system. Bioessays 15:77-83
Marusich, M F (1993) Differentiation of neurogenic precursors within the neural crest cell lineage. Brain Res Bull 30:257-63
Morrison-Graham, K; Weston, J A (1993) Transient steel factor dependence by neural crest-derived melanocyte precursors. Dev Biol 159:346-52

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