Cell migration is essential for many aspects of normal embryonic development as well as in wound healing in the adult. Failure of cells to migrate contributes to birth defects and difficulties in wound healing, whereas unregulated cell migration triggers tumor metastasis in cancer. Therefore, it is of fundamental importance to understand how cells migrate, both in normal processes and in diseases such as cancer. The long-term goal of our research is to identify critical molecules that control guided cell migration within a living organism. To this end, we study the simple migration of the border cells, a group of follicle cells in the Drosophila ovary. These cells develop from a continuous, polarized epithelium from which they break away and invade the surrounding germline. Thus, border cells are an excellent model for identifying the genetic and molecular mechanisms that control tumor invasion and metastasis. Although some of the proteins that regulate border cell migration have been identified, questions remain. For example, little is known about what regulates detachment of border cells from the epithelium. In addition, only a few molecular pathways are known to promote the polarized, dynamic protrusions that direct cell migration. To better understand how these and other aspects of border cell migration are regulated, we identified a mutation in par-1 that disrupted border cell migration in mosaic mutant clones. Par-1 is a highly conserved serine-threonine kinase that functions in cell polarity, microtubule stability, and Wnt signaling, but has not been previously implicated in regulating cell migration. In preliminary studies, we found that Par-1 functions in border cells and adjacent follicle cells and that half the border cells mutant for par-1 completely fail to migrate. Thus, Par-1 likely regulates an early step in the migration process. A known downstream target of Par-1, the Wnt signaling pathway component Disheveled (Dsh), regulates cellular protrusions in vertebrates, and we found that Dsh regulates normal border cell migration. Unexpectedly, we identified an allele of patched in a dominant genetic modifier screen of par-1-dependent border cell migration. Patched is the receptor for the Hedgehog (Hh) glycoprotein, suggesting that Hh signaling functions in Par-1-mediated border cell migration. The goal of this proposal is to further investigate the precise functions of Par-1 and its partners. We will use a powerful new live imaging technique, along with genetic, molecular and immunofluorescence techniques to address the following Specific Aims: (1) Determine the role of Par-1 in regulation of normal border cell migration;(2) Investigate the role of the Par-1 target Dsh in border cells;(3) Characterize the role of Patched in Par-1 signaling and border cell migration. These studies are anticipated to provide new insights into the mechanisms of cell migration in a living organism, which will lead to a better understanding and treatment of diseases such as cancer. Project Narrative: Cells move (migrate) in a variety of normal processes, whereas abnormally migrating cells contribute to birth defects, cannot close wounds, and trigger tumor metastasis. Using a simple model system, we found that a protein called Par-1 regulates cell invasion and migration. The goal of this study is to better understand the mechanisms that Par-1 and its protein partners use to regulate normal cell migration, with the hope that they will provide new therapeutic targets in human tumor metastasis and wound healing.
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