Regulation of axon formation by Rab10 and Arhgef7

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Neurons are highly polarized cells that establish molecularly and functionally distinct axonal and somato-dendritic compartments. Newborn postmitotic neurons initially exhibit a multi-polar morphology with several undifferentiated processes. They establish their polarized morphology by selecting one of their neurites as the axon. Neuronal polarization happens spontaneously in cultures of hippocampal neurons from the embryonic brain of rodents without requiring an input from patterned extrinsic signals. Axon extension depends the expansion of the plasma membrane by the exocytosis of specialized plasmalemma precursor vesicles (PPVs) in the growth cone. It is facilitated by the polarization of intracellular transport into the nascent axon that provides the material for growth. PPVs are present in all neurites before polarization but their exocytosis occurs preferentially in the growth cone of the nascent axon. The formation of axons is orchestrated by GTPases that regulate cytoskeletal dynamics as well as intracellular transport and exocytosis. PPVs are characterized by the presence of the GTPase Rab10 that is detectable in all neurites of unpolarized neurons but becomes enriched in the axon upon polarization. Rab10 is essential for axon formation and its knockdown prevents neuronal polarization. Prior to their exocytosis, PPVs are tethered at the plasma membrane of the growth cone by the octameric exocyst complex that is essential for axon formation. The exocyst complex is recruited to the membrane by the GTPase TC10. We have identified Arhgef7 as a GEF that activates TC10 during axon formation. When Arhgef7 is inactivated by a knockout or a knockdown, neurons fail to extend axons. In this project we will investigate the role of Rab10 GEFs, Rab10 and Argef7 for the trafficking and exocytosis of PPVs during axon formation.