Fat2 polarizes the WAVE complex in trans to align cell protrusions for collective migration

For a group of cells to migrate together, each cell must couple the polarity of its migratory machinery with that of the other cells in the cohort. Although collective cell migrations are common in animal development, little is known about how protrusions are coherently polarized among groups of migrating epithelial cells. We address this problem in the collective migration of the follicular epithelial cells in Drosophila melanogaster. In this epithelium, the cadherin Fat2 localizes to the trailing edge of each cell and promotes the formation of lamellipodia at the leading edge of the cell behind. We show that Fat2 performs this function by acting in trans to restrict WAVE complex activity to one long-lived region along each cell’s leading edge. Without Fat2, the WAVE complex distribution expands around the cell perimeter and fluctuates over time, resulting in reduced, unpolarized protrusive activity. We further show that Fat2’s influence is very local, with sub-micron-scale puncta of Fat2 concentrating the WAVE complex in corresponding puncta just across the leading-trailing cell-cell interface. These findings demonstrate that a trans interaction between Fat2 and the WAVE complex creates stable regions of protrusive activity in each cell and aligns the cells’ protrusions across the epithelium for directionally persistent collective migration.