Fat2 polarizes Lar and Sema5c to coordinate the motility of collectively migrating epithelial cells.

Migrating epithelial cells globally align their migration machinery to achieve tissue-level movement. Biochemical signaling across leading-trailing cell-cell interfaces can promote this alignment by partitioning migratory behaviors like protrusion and retraction to opposite sides of the interface. However, how the necessary signaling proteins become organized at this site is poorly understood. The follicular epithelial cells of have two signaling modules at their leading-trailing interfaces-one composed of the atypical cadherin Fat2 and the receptor tyrosine phosphatase Lar, and one composed of Semaphorin 5c and its receptor Plexin A. Here we show that these modules form one interface signaling system with Fat2 at its core. Trailing edge-enriched Fat2 concentrates both Lar and Sema5c at cells' leading edges, likely by slowing their turnover at this site. Once localized, Lar and Sema5c act in parallel to promote collective migration. Our data suggest a model in which Fat2 couples and polarizes the distributions of multiple effectors that work together to align the migration machinery of neighboring cells.