Regulation of Axon Guidance by Compartmentalized Nonsense-Mediated mRNA Decay

Abstract

SUMMARY Growth cones enable axons to navigate towards their targets by responding to extracellular signaling molecules. Growth cone responses are mediated in part by the local translation of axonal mRNAs. However, the mechanisms that regulate local translation are poorly understood. Here we show that Robo3.2, a receptor for the Slit family of guidance cues, is synthesized locally within axons of commissural neurons. Robo3.2 translation is induced by floor plate-derived signals as axons cross the spinal cord midline. Robo3.2 is also a predicted target of the nonsense-mediated mRNA decay (NMD) pathway. We find that NMD regulates Robo3.2 synthesis by inducing the degradation of Robo3.2 transcripts in axons that encounter the floor plate. Commissural neurons deficient in NMD proteins exhibit aberrant axonal trajectories after crossing the midline, consistent with misregulation of Robo3.2 expression. These data show that local translation is regulated by mRNA stability, and that NMD acts locally to influence axonal pathfinding.