Coupled local translation and degradation regulate growth cone signaling.

摘要

During development of the nervous system, neurons extend axons that travel long distances to reach their targets. To ensure proper connectivity, the growth cone at the leading edge of an axon is directed by attractive and repulsive guidance cues that mediate axon turning and pathfinding. The growing axons rely on local signaling at the growth cone to respond to guidance cues. Indeed, local translation of mRNAs that are targeted to axons has been implicated in mediating axonal elongation and pathfinding decisions in response to a variety of guidance cues. However, only a subset of the axonal proteome is locally synthesized while most axonal proteins are trafficked from the cell body. The basis for the selective translation of specific proteins in axons is unknown.;Here I show that the requirement for local translation is due to proteasomal degradation in the growth cone. I find that growth cones exhibit high levels of ubiquitination and utilize signaling pathways that rely on the ubuquitin-proteasome system (UPS). This is the case for NGF-induced outgrowth, which I find utilizes the E3 ubiquitin ligase Smurf1. A target of the UPS in axons is RhoA, which is locally translated in response to Semaphorin3A (Sema3A) and required for Sema3A-induced growth cone collapse. I find that Sema3A-induces growth cone collapse requires local synthesis of RhoA, due to its depletion by the UPS. Furthermore, stabilization of RhoA renders Sema3A-induced growth cone collapse independent of local protein synthesis. In addition to RhoA, I find that locally translated proteins are preferential targets of the UPS in growth cones. Conversely, most of the proteins that are trafficked from the cell bodies into axons are highly stable and not major targets of ubiquitination and degradation in growth cones. Thus, local translation likely serves as an adaptation to the heavy use of the UPS by signaling pathways in growth cones and provides a mechanism to restore the levels of the few proteins that are highly labile in growth cones.