miR-124 acts through coREST to control the onset of Sema3A sensitivity in navigating retinal growth cones

During axon pathfinding, growth cones commonly exhibit changes in sensitivity to guidance cues that follow a strict timetable, even in the absence of pathway feedback, implicating cell-intrinsic regulation. Cellular timer mechanisms, however, are poorly understood. Here we have investigated microRNAs in the timing control of Sema3A sensitivity in 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 (NRP-1) receptor expression, and caused cell autonomous pathfinding errors. CoREST, a cofactor of a NRP1 repressor, was identified as a novel target and mediator of miR-124 for this highly specific temporal aspect of RGC growth cone responsiveness. Our findings indicate that miR-124 plays an important role in regulating the intrinsic temporal changes in RGC growth cone sensitivity and suggest that microRNAs may play a broad role as linear timers in vertebrate neuronal development. Two independent experiments were performed. One with a single sample for each of 3 stages, and the second with 2 biological replicates of each stage.