CED-10/Rac1 mediates axon guidance by regulating the asymmetric distribution of MIG-10/lamellipodin

摘要

Axon migrations are guided by extracellular cues that induce asymmetric outgrowth activity in the growth cone [, ]. Several intracellular signaling proteins have been implicated in the guidance response [–]. However, how these proteins interact to generate asymmetric outgrowth activity is unknown. Here, we present evidence that in C. elegans, the CED-10/Rac1 GTPase binds to and causes asymmetric localization of MIG-10/lamellipodin, a protein that regulates actin polymerization and has outgrowth-promoting activity in neurons[, ]. Genetic analysis indicates that mig-10 and ced-10 function together to orient axon outgrowth. The RAPH domain of MIG-10 binds to activated CED-10/Rac1 and ced-10 function is required for the asymmetric localization of MIG-10 that occurs in response to the UNC-6etrin guidance cue. We also show that asymmetric localization of MIG-10 in growth cones is associated with asymmetric concentrations of f-actin and microtubules. These results suggest that CED-10/Rac1 is asymmetrically activated in response to the UNC-6etrin signal, thereby causing asymmetric recruitment of MIG-10/lamellipodin. We propose that the interaction between activated CED-10/Rac1 and MIG-10/lamellipodin triggers local cytoskeletal assembly and polarizes outgrowth activity in response to UNC-6etrin.