Collective migration of epithelial cells is essential for tissue morphogenesis, wound repair, and the spread of many cancers, yet how individual cells signal to one another to coordinate their movements is poorly understood. My dissertation work introduces a paradigm for regulating collective cell migration via semaphorin signaling. Semaphorins are transmembrane guidance cues that typically regulate the motility of neuronal growth cones and other migrating cells by acting as repulsive cues within the migratory environment to activate the plexin family of receptors, which are expressed in the motile cells. Studying the follicular epithelium of Drosophila revealed that a transmembrane semaphorin, Semaphorin-5c (Sema-5c), promotes collective cell migration by acting within the migrating cells themselves, not the surrounding environment. My work focused on how Sema-5c could promote migration in this unconventional manner. Here I show that Sema-5c is planar polarized within the follicular epithelium, such that it is enriched at the leading edge of each cell. This location places it in a prime position to send a signal to the trailing edge of the cell ahead, and thus communicate directional information between neighboring follicle cells during migration. My data demonstrate that Sema-5c can signal across cell-cell boundaries and this activity suppress protrusions in neighboring cells. I also find that Plexin A (PlexA) is the receptor that transduces this signal and that it is enriched at the trailing edge of each cell, the correct location to receive a signal from Sema-5c. PlexA interacts with the actin disassembly factor Mical, and I present data that are suggestive of Mical acting downstream of PlexA during follicle cell migration. Together, these data suggest that Sema-5c promotes collective motility by providing a repulsive signal from the leading edge of each cell to the trailing edge of the cell ahead. My work also revealed that Sema-5c interacts with another factor that promotes migration of the follicular epithelium, the receptor tyrosine phosphatase Lar. Like Sema-5c and PlexA, Lar is known for its role in nervous system development. Overall, my studies have uncovered a system in which multiple transmembrane guidance cues work in concert to coordinate individual cell movements for collective motility.




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