Polarized SOS activity orchestrates FGF-directed cell migration in vivo

Directed cell migration is essential for animal development and homeostasis. Cells often migrate toward or away from sources of secreted proteins that impart spatial information. How cells interpret extracellular signals to navigate to precise destinations is a fundamental question. Receptor tyrosine kinase (RTK) signaling plays critical roles in cell migration, and aberrant RTK pathway activity is implicated in many cancers. Yet how RTKs control cell migration in living animals remains unclear, in part due to the essential, pleiotropic roles of key proteins. To elucidate how RTK signaling directs cell migration in vivo, we systematically dissected the spatial and temporal requirements for key signal transduction and cytoskeletal regulatory proteins in migrating C. elegans muscle progenitors. Cell-type-specific depletion of endogenous proteins revealed that fibroblast growth factor (FGF) receptor (FGFR), growth factor receptor-bound protein 2 (GRB2), Son-of-Sevenless (SOS), and Ras homologs control cell migration independently of their canonical extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C-gamma (PLCγ) effectors. In migrating cells, SOS-1 polarity provided an intracellular readout of the direction of an FGF source, and mislocalizing SOS activity disrupted migration. By contrast, activated Ras was genetically permissive for anterior migration, and an intragenic revertant of Ras/let-60(G13E) revealed that signaling required for cell migration can be uncoupled from Ras-ERK-dependent developmental processes. Regulators of branched actin assembly controlled leading-edge dynamics but were not essential for accurate migration. Our findings provide a novel mechanism for RTK-directed cell migration and highlight the importance of cell-type-specific approaches to elucidate signal transduction mechanisms in their native contexts. This work also introduces a versatile genetic toolkit for dissecting signaling dynamics fundamental to development and disease states.