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bioRxiv · 10.1101/2025.01.22.634300

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

Sudarsanam, S.·Guzman-Clavel, L.·Dar, N.·Ziak, J.·Shahid, N.·Jin, X. O.·Kolodkin, A. L.
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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 EphA6 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/634300v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@108c788org.highwire.dtl.DTLVardef@163c6c3org.highwire.dtl.DTLVardef@18e6d8borg.highwire.dtl.DTLVardef@1b9f9e4_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIMef2c is required for the development of L4 and L5 neurons in the embryonic neocortex C_LIO_LIPostnatally, Mef2c is enriched in L2/3 neurons and is required for axon targeting C_LIO_LIL2/3-specific Mef2c deletion leads to EphA6 upregulation C_LIO_LIMef2c deletion in L2/3 neurons sensitizes them to EfnA5 repulsion in the contralateral cortex C_LI

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Sudarsanam, S., Guzman-Clavel, L., Dar, N., Ziak, J., Shahid, N., Jin, X. O., Kolodkin, A. L.. 2025-01-22. Mef2c Controls Postnatal Callosal Axon Targeting by Regulating Sensitivity to Ephrin Repulsion. https://doi.org/10.1101/2025.01.22.634300

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