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Department of Chemical and Systems Biology, Bio-X Program, Stanford University, Stanford, California 94305, USA
Growth factor-induced migration of endothelial cell monolayersenables embryonic development, wound healing, and angiogenesis.Although collective migration is widespread and therapeuticallyrelevant, the underlying mechanism by which cell monolayersrespond to growth factor, sense directional signals, inducemotility, and coordinate individual cell movements is only partiallyunderstood. Here we used RNAi to identify 100 regulatory proteinsthat enhance or suppress endothelial sheet migration into cell-freespace. We measured multiple live-cell migration parameters forall siRNA perturbations and found that each targeted proteinprimarily regulates one of four functional outputs: cell motility,directed migration, cell–cell coordination, or cell density.We demonstrate that cell motility regulators drive random, growthfactor-independent motility in the presence or absence of openspace. In contrast, directed migration regulators selectivelytransduce growth factor signals to direct cells along the monolayerboundary toward open space. Lastly, we found that regulatorsof cell–cell coordination are growth factor-independentand reorient randomly migrating cells inside the sheet whenboundary cells begin to migrate. Thus, cells transition fromrandom to collective migration through a modular control system,whereby growth factor signals convert boundary cells into pioneers,while cells inside the monolayer reorient and follow pioneersthrough growth factor-independent migration and cell–cellcoordination.