An isoform-specific function of Cdc42 in regulating mammalian Exo70 during axon formation

The highly conserved GTPase Cdc42 is an essential regulator of cell polarity and promotes exocytosis through the exocyst complex in budding yeast and Drosophila. In mammals, this function is performed by the closely related GTPase TC10, whereas mammalian Cdc42 does not interact with the exocyst. Axon formation is facilitated by the exocyst complex that tethers vesicles before their fusion to expand the plasma membrane. This function depends on the recruitment of the Exo70 subunit to the plasma membrane. Alternative splicing generates two Cdc42 isoforms that differ in their C-terminal 10 amino acids. Our results identify an isoform-specific function of Cdc42 in neurons. We show that the brain-specific Cdc42b isoform, in contrast to the ubiquitous isoform Cdc42u, can interact with Exo70. Inactivation of Arhgef7 or Cdc42b interferes with the exocytosis of post-Golgi vesicles in the growth cone. Cdc42b regulates exocytosis and axon formation downstream of its activator Arhgef7. Thus, the function of Cdc42 in regulating exocytosis is conserved in mammals but specific to one isoform.