The long-term objective of this application is to understand how transcription factors control the development of neural crest-derived pigment cells, or melanocytes, in the vertebrate embryo. By acting at the level of the nucleus and binding to defined DNA elements on promoter or enhancer regions of genes, transcription factors have the ability to interact with the basal transcriptional machinery to activate or repress transcription. Transcription of entire sets of genes can be influenced by the actions of individual transcription factors, leading to the activation or repression of gene programs that have the ability to determine major characteristics of a developing cell. Genetic and biochemical data from well-established murine coat color mutants and from patients with congenital disorders of pigmentation all support the important role of transcription factors in promoting the proper development of the melanocyte, a cell which not only confers pigment to the skin and hair, but also promotes the proper development of the eye and inner ear as well.
The specific aims of this proposal are to understand the function of the transcription factors Mitf and Pax3 in melanocyte development and to determine how the misexpression of a basic helix-loop-helix transcription factor in melanocyte precursors affects both melanocyte development and differentiation. Achieving these aims, using a combination of techniques with transgenic animals, primary cultures of neural crest cells, and molecular methods of gene expression analysis, will enhance findings from previous work that has been performed in this field and will help elucidate the mechanisms whereby transcription factors known to be crucial to the development of the melanocytic lineage function during development. They will also help determine how factors known to perturb melanocyte development and differentiation act in this role. The results of these experiments have the potential to contribute to our understanding of the etiology of certain genetic disorders of pigmentation, the regulation of normal pigmentation, and the genesis of proliferative melanocytic lesions with substantial morbidity such as large congenital melanocytic nevi and malignant melanoma.
