Adhesion and Cytoskeleton Dynamics in Cell Migration

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DESCRIPTION (provided by applicant): Properly regulated cell migrations are essential to human health. Genetic defects that impair cell motility cause birth defects such as brain malformations and immune deficiencies. On the other hand, the ability to migrate and invade converts curable tumors into incurable, metastatic disease. In addition, in order to achieve a major goal of regenerative medicine, which is the creation of artificial organs and tissues, it is necessary not only to specify all of the appropriate cell types, but also to control their organization, communication, and movements. Therefore it is of great importance that we understand and harness the mechanisms controlling tissue morphogenesis in general, and cell migration in particular. These are the long-term goals of our studies. Decades of research have revealed the molecules and mechanisms that control the movements of single cells in tissue culture dishes. How cells move through their intricate natural environments is less well-understood. In vivo cells often move in interconnected sheets, tubes, strands, and clusters. Despite their ubiquity and importance, such collective cell behaviors are not as well-studied as those of single cells. The shapes of cells moving through complex environments can differ greatly from the morphology of a cell migrating, unobstructed, on glass. These observations raise numerous questions. For example, how do the mechanisms of collective cell movement resemble or differ from single cell motility, and how is the great diversity of cell shapes achieved? One major difference between single and collective cell migration is that cells moving collectively maintain cell-cell adhesion even as they move. While we now know many of the molecules that are important for cell movements, we know far less about how the activities of these proteins are coordinated in space and time. To address these questions we have developed a relatively simple and genetically tractable model for the study of collective cell migration: the border cells in the Drosophila ovary. We propose to use new methods that we have developed to measure and even manipulate protein activities and mechanical forces in vivo with light. Our specific aims are to: 1) test the hypothesis that cell-cell adhesion serves multiple, critical functions in collectively migrating cells, including cluster organization, direcion sensing, and stabilization of protrusions. We will also compare directly the mechanisms of single and collective cell migration in vivo. 2) test the hypothesis that feedback between Rac and a tyrosine kinase coordinates polarity, protrusion, and adhesion during collective migration. Here we also propose to identify functional substrates of the tyrosine kinase. 3) test the "Tropomyosin (Tm) code hypothesis," which postulates that the diversity of cell shapes and behaviors can be attributed to the diversity of dynamic F-actin structures, which in turn depend upon the combination of Tm isoforms present in a cell.