Molecular and Cellular Control of Collective Cell Migration.

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ABSTRACT During embryonic development, cells often move in groups to assemble into tissues and organs. They are guided by attractant gradients and coordinate their migration to move in a directed manner. How attractant gradients are maintained and how cells in migrating groups coordinate their movements is unclear. To address these questions, we use the posterior lateral line primordium migration in zebrafish as a model. The primordium is a group of about 100 cells, which express the chemokine receptor Cxcr4 and follow a trail of Sdf1 chemokine. We have used this system to show that the primordium generates an Sdf1 gradient across itself by sequestering Sdf1 in its rear through the alternate Sdf1 receptor Cxcr7, a chemokine scavenger receptor. In Aim 1, we will determine how Sdf1 levels are controlled by the chemokine clearance receptor Cxcr7 using an Sdf1 signaling sensor that we developed. The cells in the primordium also express cadherins and adhere to each other tightly. In Aim 2, we will analyze the role of cadherins in coordinating collective migration and use cadherin-based tension sensors to measure the tension forces between the cells in the primordium. Our approach combines the optical accessibility of the zebrafish primordium with quantitative imaging, embryonic and genetic manipulations, and novel sensors for chemokine signaling and tension forces to provide a quantitative understanding of the molecular and cellular mechanisms underlying collective cell migration. We anticipate that our proposed studies will have two broad impacts on the field of cell migration. First, they will provide a quantitative understanding of how attractant gradients are regulated. Second, they will unravel the mechanics of cell-cell adhesion in a migrating tissue. These insights are key to understanding major biological and medical problems including defects in embryogenesis, organogenesis, and cancer metastasis.