New roles for old proteins in actin-mediated cell migration.

摘要

Cell migration is a fundamental process for normal embryonic development and maintenance of the adult organism. Despite these required and favorable aspects of cell migration, unwanted cell migration events can also occur. One example of this is tumor metastasis. Understanding genes that are required for these processes will lead us to a better understanding of basic biology as well as potential targets for cancer treatment. We study a group of migrating cells, called the border cells, in the Drosophila ovary as a model system to study cell migration. My thesis work has focused on the study of two genes required for border cell migration, jaguar, which encodes for Myosin VI, and DRacA.; Myosin VI is expressed in epithelial follicle cells and migrating border cells. Expression of an anti-sense Myosin VI specifically in the border cells results in dramatic border cell migration defects. Unexpectedly, expression of the cell adhesion molecule DE-cadherin (Cad) and its binding partner Armadillo (Arm) are reduced in border cells depleted for Myosin VI. Outer follicle cells depleted for Myosin VI show decreased Cad and Arm protein levels. In addition, outer follicle cells mutant for shotgun (the gene that encodes Cadherin) and armadillo show decreased levels of Myosin VI protein. Biochemically, Myosin VI is in a complex with Cad and Arm and directly interacts with Arm. Interestingly, actin protrusions are not present in border cells depleted for Myo VI, suggesting the possibility that Myosin VI may be required for mediating actin protrusions in border cell migration.; Rac is a GTPase well-known for its involvement in cell migration. Rac is required for regulation of the actin cytoskeleton at the leading edge of migrating cells. In Drosophila, Rac is required for dorsal closure, axon guidance, and border cell migration. Mutants null for the Rac1 and Rac2 genes show border cell migration defects. In addition, expression of a dominant-negative form of Rac (RacN17) results in border cell migration defects. We used this latter observation as the basis for a genetic suppression screen. Three genes emerged from the screen that when overexpressed, rescue the RacN17 border cell migration phenotype: hedgehog, actin 5C, and thread, which encodes for the Drosophila Inhibitor of Apoptosis (DIAP1). Mutations in all three genes show border cell migration defects. The role of Hedgehog in migration and its relationship to Rac is under investigation. However, DIAP1 binds in a complex with Rac and Profilin to stimulate actin polymerization, independent of apoptosis.