miR-182 Regulates Slit2-Mediated Axon Guidance by Modulating the Local Translation of a Specific mRNA

During brain wiring, cue-induced axon behaviors such as directional steering and branching are aided by localized mRNA translation. Different guidance cues elicit translation of subsets of mRNAs that differentially regulate the cytoskeleton, yet little is understood about how specific mRNAs are selected for translation. MicroRNAs (miRNAs) are critical translational regulators that act through a sequence-specific mechanism. Here, we investigate the local role of miRNAs in mRNA-specific translation during pathfinding of $\textit{Xenopus laevis }$ retinal ganglion cell (RGC) axons. Among a rich repertoire of axonal miRNAs, miR-182 is identified as the most abundant. Loss of miR-182 causes RGC axon targeting defects in vivo and impairs Slit2-induced growth cone (GC) repulsion. We find that miR-182 targets cofilin-1 mRNA, silencing its translation, and Slit2 rapidly relieves the repression without causing miR-182 degradation. Our data support a model whereby miR-182 reversibly gates the selection of transcripts for fast translation depending on the extrinsic cue.This study was supported by EMBO ( ALTF992-2011 ) and HFSP fellowships ( LT000136/2012 ) (to A.B.), University of Trento PhD studentship (to A.I.), Wellcome Trust Programme ( 085314/Z/08/Z ) (to C.E.H.), and Marie Curie Career Integration ( 618969 GUIDANCE-miR ), G. Armenise-Harvard Foundation Career, and MIUR SIR ( RBSI144NZ4 ) grants (to M.-L.B.)