title: miR-124 acts through CoREST to control onset of Sema3A sensitivity in navigating retinal growth cones.
abstract: During axon pathfinding, growth cones commonly show changes in sensitivity to guidance cues that follow a cell-intrinsic timetable. The cellular timer mechanisms that regulate such changes are, however, poorly understood. Here we have investigated microRNAs (miRNAs) in the timing control of sensitivity to the semaphorin Sema3A in Xenopus laevis retinal ganglion cell (RGC) growth cones. A developmental profiling screen identified miR-124 as a candidate timer. Loss of miR-124 delayed the onset of Sema3A sensitivity and concomitant neuropilin-1 (NRP1) receptor expression and caused cell-autonomous pathfinding errors. CoREST, a cofactor of a NRP1 repressor, was newly identified as a target and mediator of miR-124 for this highly specific temporal aspect of RGC growth cone responsiveness. Our findings indicate that miR-124 is important in regulating the intrinsic temporal changes in RGC growth cone sensitivity and suggest that miRNAs may act broadly as linear timers in vertebrate neuronal development.
authors.affiliation: Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Baudet
authors.forename: Krishna H
authors.initials: KH
authors.lastname: Zivraj
authors.forename: Cei
authors.initials: C
authors.lastname: Abreu-Goodger
authors.forename: Alistair
authors.initials: A
authors.lastname: Muldal
authors.forename: Javier
authors.initials: J
authors.lastname: Armisen
authors.forename: Cherie
authors.initials: C
authors.lastname: Blenkiron
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Goldstein
authors.forename: Eric A
authors.initials: EA
authors.lastname: Miska
authors.forename: Christine E
authors.initials: CE
authors.lastname: Holt
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D020439:Growth Cones / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D040121:Semaphorin-3A; D039942:Neuropilin-1