LINEAGE DETERMINATION IN NEURAL CREST DEVELOPMENT

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The purpose of this application is to provide support for research training to enable me to become an independent biomedical investigator. Having completed most of my clinical training in dermatology, I plan to shift my research interests from protein chemistry, the subject of my Ph.D. training, to molecular and cellular biology by studying the molecular biology of neural crest development in the laboratory of Edward B. Ziff, Ph.D., Professor of Biochemistry at NYU Medical Center and an Investigator of the Howard Hughes Medical Institute. During the training period, l will hold a faculty appointment in the Department of Dermatology at NYU, chaired by Irwin M. Freedberg, M.D. When the training period is complete, I hope to be an independently-funded, tenure-track investigator at a major medical center. The goal of the research project is to understand molecular events governing early development of the neural crest, particularly melanocytes. The regulation of the tyrosinase-related protein 2 (TRP-2) gene will be studied. In the mouse embryo, TRP-2 is expressed several days before markers of terminal melanocyte differentiation. Expression vectors containing fragments of the TRP-2 promoter will be transfected into melanocytes and the activity of the promoter observed. DNA elements important for TRP-2 expression will be identified, facilitating the identification of transcription factors important for early melanocyte- specific gene expression. In a parallel study, the TRP-2 promoter will be used to drive the expression of MASH-1, a neuron-specific gene. The results of these studies may be applicable to several areas of human health. Identification of factors responsible for early gene expression in the neural crest may increase our understanding of certain congenital syndromes of hypopigmentation and deafness. Melanoblasts possess tremendous migratory capacity during initial migration from the neural crest, and understanding the basis for this migration may lead to new insights about the invasiveness of malignant melanoma cells as well.