Sudarsanam Sriram, Guzman-Clavel Luis, Dar Nyle, Ziak Jakub, Shahid Naseer, Jin Xinyu O, Kolodkin Alex L
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins Kavli Neuroscience Discovery Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
These authors contributed equally.
bioRxiv. 2025 Jan 22:2025.01.22.634300. doi: 10.1101/2025.01.22.634300.
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, expression shifts to layer 2/3 callosal projection neurons (L2/3 CPNs), and we find a novel function for in targeting homotopic contralateral cortical regions by S1-L2/3 CPNs. We demonstrate, using functional manipulation of EphA-EphrinA signaling in mutant CPNs, that Mef2c downregulates 6 to desensitize S1-L2/3 CPN axons to EphrinA5-repulsion at their contralateral targets. Our work uncovers dual roles for in cortical development: regulation of laminar subtype specification during embryogenesis, and axon targeting in postnatal callosal neurons.
皮质连接依赖于神经元亚型的有序出现，随后形成亚型特异性轴突投射。包括长程胼胝体投射在内的皮质内回路对信息处理至关重要，但皮质内轴突靶向的机制仍不清楚。我们发现转录因子肌细胞增强因子2-c（Mef2c）在胚胎发育过程中指导体感皮质（S1）第4层和第5层锥体神经元的发育。在出生后早期发育过程中，表达转移到第2/3层胼胝体投射神经元（L2/3 CPNs），并且我们发现其在S1-L2/3 CPNs靶向同侧对侧皮质区域方面具有新功能。我们通过对突变CPNs中EphA-EphrinA信号进行功能操作证明，Mef2c下调6以使S1-L2/3 CPN轴突在其对侧靶点对EphrinA5排斥不敏感。我们的工作揭示了其在皮质发育中的双重作用：在胚胎发育过程中调节层状亚型特异性，以及在出生后胼胝体神经元中进行轴突靶向。
