Epithelial to mesenchymal transitions are critical features of the development of most organs and tissues, however the molecular basis of this phenomenon is not well understood. In addition, most tumors are of epithelial origin and acquisition of an invasive phenotype is a critical, but relatively poorly understood step in metastasis. We have developed a model system for a systematic genetic approach to the study of epithelial to mesenchymal transitions. Studies from my lab and others indicate that the conversion of border cells in the Drosophila ovary from epithelial cells to migratory cells is a multistep process that depends upon changes in gene expression, cell adhesion and cytoskeletal organization. The first gene identified to play a role in border cell migration, slow border cells (slbo), encodes a Drosophila homolog of the C/EBP family of transcription factors. SLBO regulates the expression of a number of target genes including those that code for an FGF receptor homolog and E cadherin. In addition, the regulated activity of the GTPase Rac, but not Rho or Cdc42, is required during border cell migration. We have recently discovered a SLBO independent pathway, defined by three loci, taiman (tai), slow motion (slmo) and stuck in place (sip) that were identified in a screen for mutations that cause cell migration defects in mosaic clones. These loci exhibit dominant genetic interactions, indicating that they may act in a common biochemical pathway. The tai gene encodes a protein homologous to steroid hormone receptor coactivators, the first such protein identified in an invertebrate. In tai mutants the expression and subcellular localizations of a number of border cell proteins are unchanged, whereas Armadillo (ARM) protein levels remain unusually high, suggesting a possible explanation for the migration defect.
The specific aims of this proposal are to 1) test the hypothesis that failure to down regulate ARM expression contributes to the tai migration defect; 2) test the hypothesis that TAI is a hormone dependent transcriptional regulator; 3) define the roles of slmo and sip in border cell migration; and 4) identify and characterize proteins that act in the Rac pathway to affect border cell migration.
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