Mef2c Controls Postnatal Callosal Axon Targeting by Regulating Sensitivity to Ephrin Repulsion

Cortical connectivity is contingent on ordered emergence of neuron subtypes followed by the formation of subtype-specific axon projections. Intracortical circuits, including long-range callosal projections, are crucial for information processing, but mechanisms of intracortical axon targeting are still unclear. We find that the transcription factor Myocyte enhancer factor 2-c (Mef2c) directs the development of somatosensory cortical (S1) layer 4 and 5 pyramidal neurons during embryogenesis. During early postnatal development,Mef2cexpression shifts to layer 2/3 callosal projection neurons (L2/3 CPNs), and we find a novel function forMef2cin targeting homotopic contralateral cortical regions by S1-L2/3 CPNs. We demonstrate, using functional manipulation of EphA-EphrinA signaling inMef2c-mutant CPNs, that Mef2c downregulatesEphA6 to desensitize S1-L2/3 CPN axons to EphrinA5-repulsion at their contralateral targets. Our work uncovers dual roles forMef2cin cortical development: regulation of laminar subtype specification during embryogenesis, and axon targeting in postnatal callosal neurons.<fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="634300v1_ufig1" position="float" orientation="portrait"/></fig>