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.Axons navigate in a complex and changing environment to establish connections with their targets. Chemotropic cues in this environment attract and repel growing axons 1,2 , and growth cones must modulate their responsiveness en route to avoid stalling at attractive intermediate targets or invading non-targets. Growth cones of commissural neurons in the vertebrate spinal cord, for example, are initially attracted to Netrin-1 and unresponsive to Slits, but, after crossing the midline (an intermediate target), they become unresponsive to Netrin-1 and repelled by Slits 3,4 . Similarly, RGC axons change their responsiveness to several cues as they advance along the pathway 5-7 with growth cones initially showing attraction to Netrin-1 and neutral responses to repellents (Sema3A and Slit2) and later

Differential Properties of Transcriptional Complexes Formed by the CoREST Family

“…The presence of CoREST in the complex is essential for the recognition of the nucleosomal substrate and its deacetylation and demethylation by HDAC1/2 and LSD1/KDM1A, respectively (14)(15)(16)(17). CoREST is highly preserved throughout evolution, and homologs in Drosophila (18), Xenopus (19), and Caenorhabditis elegans (20), where it regulates specific cell phenotypes acquisition (18,(20)(21)(22), have been described. In humans, CoREST is encoded by the gene rcor1 and has 482 amino acids with a molecular mass of 66 kDa (1).…”

ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A

“…They can lose the ability to respond to a cue that they initially responded to and acquire the ability to react to others 3,4 . Often, axons switch responsiveness by modulating the repertoire of receptors expressed at their growth cones [5][6][7][8][9][10] .…”

Noggin 1 overexpression in retinal progenitors affects bipolar cell generation

“…Electroporation experiments were carried out at stage 26 (Falk et al, 2007;Baudet et al, 2011). At this stage, the optic vesicles have detached from electroporation of neither GFP alone nor GFP + Noggin1 affected D/V or A/P axes with respect to wild-type controls at both stages analysed (Fig.…”