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

Intracortical circuits, including long-range callosal projections, are crucial for information processing. The development of neuronal connectivity in the cerebral cortex is contingent on ordered emergence of neuronal classes followed by the formation of class-specific axon projections. However, the genetic determinants 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 identity in murine postmitotic pyramidal neurons during embryogenesis. During postnatal development, <i>Mef2c</i> expression shifts to Layer 2/3 callosal projection neurons (L2/3 CPNs). At this later developmental stage, we identify a novel function for <i>Mef2c</i> in contralateral homotopic domain targeting by S1-L2/3 CPN axons. We employ functional manipulation of EphrinA-EphA signaling in <i>Mef2c</i> mutant CPNs and demonstrate that Mef2c represses <i>EphA</i>6 to desensitize S1-L2/3 CPN axons to EphrinA5 repulsion at their contralateral targets. Our work uncovers dual roles for <i>Mef2c</i> in cortical development: regulation of laminar subtype specification during embryogenesis and axon targeting in postnatal callosal neurons.