The Role of Ets1 in Melanocyte Development

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DESCRIPTION (provided by applicant): Melanocytes are derived from pluripotent neural crest (NC) cells, which arise from the dorsal aspect of the neural tube. Although NC cells are initially pluripotent, their differentiation potential gradually becomes restricted depending on intrinsic factors and cues they encounter during their migration. Several genes have been identified that are involved in the specification of melanocytes from the NC through the study of mouse pigmentation mutants. Mutations in the transcription factors Pax3, Sox10, and Mitf result in hypopigmentation phenotypes in mice and humans. Recently, the deletion of the transcription factor Ets1 was shown to produce cardiac malformations as a result of improper NC cell development. Furthermore, Ets1 null and heterozygous mice exhibit ventral hypopigmentation, hinting to the involvement of this transcription factor in melanocyte development from the NC. Ets1 is a widely expressed helix-turn-helix transcription factor which recognizes the nucleotide sequence GGAA/T. It is expressed in various developing organs and tissues in the mouse embryo, including the NC. Ets1 has been implicated in diverse processes, including cell proliferation, apoptosis, differentiation, lymphoid cell development, angiogenesis, and invasiveness. The main goal of the proposed study is to characterize the role played by Ets1 in melanocyte development. We will (1) Determine the temporal requirement and mechanism of action of Ets1 in the development of the melanocyte lineage. (2) Identify genetic and molecular interactions between Ets1 and melanocytic genes. To accomplish these aims we will use a combination of in vivo and in vitro proliferation, apoptosis and migration assays. Additionally, we will perform genetic crosses, promoter analysis and binding assays to evaluate the interaction of Ets1 with Sox10, Pax3, and Mitf. Our results have the potential to uncover a new role for Ets1 and establish a more complete picture of the transcriptional network that controls melanocyte development. Besides their relevance for understanding fundamental principles of cell lineage specification, our studies will also be relevant for the understanding of developmental disorders involving the NC and skin pigmentation. PUBLIC HEALTH RELEVANCE: Neural crest cells give rise to a variety of cell types and the abnormal development of these cells can result in several congenital conditions including sensorineural deafness, cranio-facial abnormalities, cardiac malformations, impaired thyroid and tongue, and pigmentation disorders. The characterization of the role played by the transcription factor Ets1 in neural crest cells and melanocytes will help further delineate the fundamental errors that underlie some of these disorders and possibly contribute to the development of targeted therapies.