Integrin signaling switches the cytoskeletal and exocytic machinery that drives neuritogenesis.

Neurons establish their unique morphology by elaborating multiple neurites that subsequently form axons and dendrites. Neurite initiation entails significant surface area expansion, necessitating addition to the plasma membrane. We report that regulated membrane delivery coordinated with the actin cytoskeleton is crucial for neuritogenesis and identify two independent pathways that use distinct exocytic and cytoskeletal machinery to drive neuritogenesis. One pathway uses Ena/VASP-regulated actin dynamics coordinated with VAMP2-mediated exocytosis and involves a novel role for Ena/VASP in exocytosis. A second mechanism occurs in the presence of laminin through integrin-dependent activation of FAK and src and uses coordinated activity of the Arp2/3 complex and VAMP7-mediated exocytosis. We conclude that neuritogenesis can be driven by two distinct pathways that differentially coordinate cytoskeletal dynamics and exocytosis. These regulated changes and coordination of cytoskeletal and exocytic machinery may be used in other physiological contexts involving cell motility and morphogenesis.