Regulation of Axon Guidance by Compartmentalized Nonsense-Mediated mRNA Decay

Growth cones enable axons to navigate toward their targets by responding to extracellular signaling molecules. Growth-cone responses are mediated in part by the local translation of axonal messenger RNAs (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. [Display omitted] •Robo3.2 is locally synthesized in growth cones of commissural axons•NMD proteins are enriched in growth cones of diverse types of neurons•NMD regulates the amount of Robo3.2 synthesized in growth cones•Defects in NMD lead to abnormal axonal trajectories in spinal cord In growth cones of spinal-cord commissural neurons, the levels of the axon guidance receptor Robo3.2 are regulated by nonsense-mediated mRNA decay (NMD), with defects in NMD leading to abnormal axonal trajectories.