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

ABSTRACT 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, Mef2c expression shifts to layer 2/3 callosal projection neurons (L2/3 CPNs), and we find a novel function for Mef2c in targeting homotopic contralateral cortical regions by S1-L2/3 CPNs. We demonstrate, using functional manipulation of EphA-EphrinA signaling in Mef2c- mutant CPNs, that Mef2c downregulates EphA 6 to desensitize S1-L2/3 CPN axons to EphrinA5-repulsion at their contralateral targets. Our work uncovers dual roles for Mef2c in cortical development: regulation of laminar subtype specification during embryogenesis, and axon targeting in postnatal callosal neurons. HIGHLIGHTS Mef2c is required for the development of L4 and L5 neurons in the embryonic neocortex Postnatally, Mef2c is enriched in L2/3 neurons and is required for axon targeting L2/3-specific Mef2c deletion leads to EphA6 upregulation Mef2c deletion in L2/3 neurons sensitizes them to EfnA5 repulsion in the contralateral cortex