Neural crest cells emigrate from the neural tube and give rise to numerous derivatives, each of which migrate and localize to specific sites during embryoqenesis. Our long-term goal is to determine how these various derivatives come to occupy the correct position in the embryo. One model for patterninq neural crest derivatives proposes that pluripotent neural crest cells migrate haphazardly into the various pathways and differentiate according to cues encountered in these paths. However, our studies have revealed, contrary to this model, that melanoblasts (pigment cell precursors derived from the neural crest) are specified at the time they leave the trunk-level neural tube and are therefore not pluripotent. Moreover, this prior specification confers upon melanoblasts the ability to migrate into the dorsolateral pathway (i.e. the path to the skin) whereas other neural crest subpopulations (those destined to be neural or glial cells) are prohibited from entering the dorsolateral path and instead migrate ventrally. We will determine the cellular mechanisms by which melanoblasts can invade the dorsolateral space to the exclusion of other neural crest cells. Our model is that ephrin-Bs inhibit neural/glial precursors from migrating in the dorsolateral path, but promote melanoblast migration, and that ephrin-As produced by the dermatome reinforce directed melanoblast migration by establishing a chemotactic gradient. This proposal has two specific aims. 1) To determine how EphB/ephrin-B signaling regulates trunk neural crest migratory behavior. 2) To assess the role of ephrin-As as chemoattractants for melanoblasts. We will accomplish these aims by regulating gene expression using the recently developed technique of electroporation of expression vectors, in combination with classic experimental manipulation of the chicken embryo. These studies will focus on the mechanisms by which different subpopulations of neural crest cells (melanocytes, neurons, glial cells) find their way to the appropriate site during embryogenesis. Defects in pathfinding of the neural crest give rise to a host of birth defects and developmental abnormalities, such as pigmentation defects, craniofacial abnormalities, colon defects, including Hirschsprung's disease, and a vast array of cardiac and great vessel malformations. Understanding the fundamental mechanisms by which the neural crest cells are properly positioned will allow us to understand the underlying basis of these common birth defects.
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