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 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.
PDN Department, University of Cambridge, Cambridge CB23DY, UK.
Anaïs
A
Bellon
CIBIO, University of Trento, Trento 38123, Italy.
Archana
A
Iyer
CIBIO, University of Trento, Trento 38123, Italy.
Simone
S
Bridi
PDN Department, University of Cambridge, Cambridge CB23DY, UK.
Flora C Y
FCY
Lee
Unidad de Genómica Avanzada (Langebio), Cinvestav, Irapuato 36821, Mexico.
Cesaré
C
Ovando-Vázquez
CIBIO, University of Trento, Trento 38123, Italy.
Eloina
E
Corradi
CIBIO, University of Trento, Trento 38123, Italy.
Sara
S
Longhi
CIBIO, University of Trento, Trento 38123, Italy.
Michela
M
Roccuzzo
CIBIO, University of Trento, Trento 38123, Italy.
Stephanie
S
Strohbuecker
CIBIO, University of Trento, Trento 38123, Italy.
Sindhu
S
Naik
Gurdon Institute, University of Cambridge, Cambridge CB21QN, UK.
Peter
P
Sarkies
Gurdon Institute, University of Cambridge, Cambridge CB21QN, UK.
Eric
E
Miska
Unidad de Genómica Avanzada (Langebio), Cinvestav, Irapuato 36821, Mexico.
Cei
C
Abreu-Goodger
PDN Department, University of Cambridge, Cambridge CB23DY, UK. Electronic address: ceh33@cam.ac.uk.
Christine E
CE
Holt
CIBIO, University of Trento, Trento 38123, Italy. Electronic address: marielaure.baudet@unitn.it.
Marie-Laure
ML
Baudet
D000818:Animals; D000071437:Axon Guidance / Q000502:physiology*; D001369:Axons / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020439:Growth Cones / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D014982:Xenopus laevis / Q000378:metabolism; D000098552:Slit Homolog 2 Protein
D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000098552:Slit Homolog 2 Protein
Slit2; axon guidance; brain wiring; cofilin; growth cone; local translation; miR-182; miRNAs