The long-term goal of this research is to understand how stable differences in developmental ability are established in the neural crest (NC) cell lineage of vertebrate embryos. 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, and Schwann sheath cells and glia of the peripheral ganglia. In contrast, trunk NC cells that disperse lateron a dorsolateral (""""""""lateral"""""""") pathway never give rise to neuronal derivatives. The principal investigator has learned that developmentally-distinct subpopulations of crest-derived cells are present early in migrating crest populations. One of these subpopulations--neurogenic precursors--appears transiently among the earliest premigratory cells. Neurogenic precursors transiently require trophic support for survival. They appear to disperse exclusively on the medial migration pathway, and ultimately give rise to a variety of neuronal phenotypes in peripheral ganglia. In the next grant period, the principal investigator will test the hypothesis that developmental cues in the embryonic environment selectively regulate survival, dispersal, and differentiation of specified neurogenic precursors. In addition, the principal investigator will characterize the molecular mechanisms involved in regulating the segregation and fate of these neurogenic precursors in the crest lineage. Specifically, the principal investigator proposes: (1) to combine cell- lineage analysis and neuron-specific molecular markers to characterize the initial segregation of neurogenic precursors in the neural crest lineage; (2) to examine the role of specific environmental cues (retinoic acid, NT-3, and BDNF) and their receptors in the segregation and subsequent survival of crest-derived neurogenic precursors; (3) to assess the function of members of the neuron-specific (Hu) family of RNA-binding proteins in neuronal differentiation by examining the consequences of Hu misexpression in neural crest-derived cells; and (4) to identify early molecular markers of neuronal specification and differentiation in neural crest-derived neurogenic precursors.
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