Transcriptional regulation of NC precursor formation

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DESCRIPTION (provided by applicant): Neural crest cells are multi-potent, migratory, tissue-invasive cells that originate in the ectoderm of vertebrate embryos and play a central role in the development of the vertebrate body plan. A number of devastating cancers, including melanoma and neuroblastoma, are cancers of the neural crest. Moreover, neural crest cells share a number of general characteristics with metastatic tumor cells, and these two cell types have key molecular mediators in common, including Snail-family repressors and c-myc. This proposal seeks to exploit the considerable advantages of the Xenopus system in order to better understand the roles played by Snail-related factors and c-myc during normal neural crest development and in tumorigenesis, including the acquisition of invasiveness. The aims of the grant include: 1) determining the molecular mechanisms that underlie the distinct activities of Snail-family proteins during neural crest precursor formation, neural crest emigration, and during epithelial-to-mesenchymal transitions (EMTs) in tumor cells; 2) determining if c-myc regulates the expression of neural crest target genes by recruiting HAT activity to target promoters, and determining if Id3 functions as a Myc-effector during neural crest formation; 3) using cDNA macroarray-based gene discovery methods to identify the key transcriptional targets of c-myc and Snail-family repressors during neural crest precursor cell formation, and during the onset of neural crest migration and 4) testing the hypothesis that such targets will also play roles in tumor progression by examining the expression of these factors, and the effects of over-expressing these factors, in a panel of epithelial tumor cell lines