Phosphatase Control of Collective Cell Migration during Development

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Cells move and migrate to new locations in the bodies of developing animals, an important step for the correct formation and function of organs. The proposed research uses a simple genetic model, the fruit fly, to investigate how cells move as organized groups within the animal. The overall goal of these studies is to identify fundamental mechanisms that keep cells together during cell movement, a poorly understood process. Results from these studies are expected to shed light on the way that cells migrate to populate tissues and organs during animal development. A major impact of the proposed project is the training of students and encouragement of underrepresented groups to pursue scientific-intensive careers. Because of the ease of use and available genetic tools, these studies with the fruit fly model are ideally suited for the training of students. The McDonald lab has a history of training undergraduate and graduate students from diverse backgrounds, and will continue to do so in the proposed studies. The investigator will specifically recruit female and underrepresented minority undergraduate students from three local institutions that currently offer limited research opportunities. The project also includes several outreach efforts, based on the proposed research, to a local grade school and high school comprised mainly of underrepresented minorities. These activities together will introduce students to research in genetics and animal cell and developmental biology and encourage them to pursue scientific and technical careers.Throughout development cells frequently move in groups to form, shape and remodel tissues and organs. Such "collectively" migrating cells adhere strongly to one another but also coordinate movement of the whole group as a single unit. Despite their crucial importance to development, how cells migrate collectively rather than individually remains poorly characterized. Drosophila border cells represent a genetically accessible model for the discovery of fundamental regulatory pathways that underlie collective cell movement. Dynamic cycles of phosphorylation and dephosphorylation regulate the cellular signaling pathways and physical/cytoskeletal dynamics involved in individual and collective cell migration. While the functions of protein kinases are well established, much less is known about the roles of protein phosphatases. Novel preliminary data indicate that protein phosphatase activity is an unanticipated controller of collective cohesion and migration of border cells. Border cells in which phosphatase activity is inhibited round up, break off from the main group and are unable to complete their migration. The central hypothesis of this proposal is that distinct phosphatase complexes maintain a collective mode of migration through dynamic regulation of identifiable substrates. The proposed project combines genetic, live imaging, cell biology and biochemical approaches to determine which phosphatase complexes regulate collective border cell migration. Moreover, these studies will identify phosphatase target proteins responsible for the collective cohesion and migration of border cells. As common mechanisms underlie different collective cell migration processes, the proposed studies utilizing the powerful border cell model will uncover new cellular and molecular pathways regulated by protein phosphatases. Together, this will critically advance knowledge of how organs form and are remodeled by collectives during development of multicellular organisms.