Our long-term goal is to understand how stable differences in developmental ability are established in the neural crest (NC) cell lineage. When trunk NC cells segregate from neural tube epithelium in vivo, they enter a cell-free, extracellular matrix-rich """"""""migration staging area"""""""" (MSA), and then disperse on two distinct migration pathways. Trunk NC cells that disperse early on a medioventral (""""""""medial"""""""") pathway between the neural tube and the somites give rise to both neuronal and non- neuronal derivatives. These include sensory, autonomic and enteric neurons, Schwann sheath cells and glia of the peripheral ganglia, and perhaps some late-developing melanocytes in distal locations. In contrast, trunk NC cells that disperse later on a dorsolateral (""""""""lateral"""""""") pathway never give rise to neuronal derivatives, but differentiate only as melanocytes (and perhaps other non-neuronal) crest derivatives. We have found that crest-derived melanocyte precursors express c-kit, the receptor for Steel Factor (SLF), and transiently depend on SLF function for survival in vitro. Previous work, by us and others, has also shown that differentiation of melanocytes and other non-neuronal, crest-derived cells is affected both by SLF and by platelet-derived growth factor (PDGF) function, mediated by the receptor PDGFRalpha. To explain why melanocytes arise primarily (or solely) from NC cells on the lateral pathway of mouse embryos, we hypothesize that developmentally-distinct crest-derived cells, which appear at late stages of crest cell dispersal from the MSA , selectively follow the lateral crest-migration pathway where they encounter localized growth/survival cues that they require. To test this hypothesis, we will examine murine embryos during crest cell dispersal, and cultured crest cells at corresponding developmental stages, to learn (a) when and where crest-derived melanocyte precursors first acquire the receptors for Steel factor (c-kit) and platelet-derived growth factor, A- chain (PDGFRalpha), (b) when and where crest cells encounter SLF and PDGF during their initial dispersal in embryonic interstitial spaces, and (c) how mutational perturbation of SLF presentation affects developmental behavior of melanocyte precursors. Specifically, we will: 1. characterize the expression of c-kit and PDGFRalpha in late-migrating (non-neurogenic) crest-derived cells in vitro; 2. determine the distribution of SLF and PDGF on the medial and lateral crest migratory pathways in the embryonic trunk, and the pattern of dispersal of crest-derived melanocyte precursors on these two pathways; and concurrently, 3. characterize the pattern of dispersal and the fate of crest-derived melanocyte precursors when SLF and PDGF function are mutationally perturbed in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE004316-20
Application #
2713254
Study Section
Special Emphasis Panel (ZRG2-HED-2 (01))
Project Start
1997-05-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
20
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Oregon
Department
Neurosciences
Type
Schools of Arts and Sciences
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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