Med13 is involved in the radial migration and contralateral projection of cortical neurons via PlxnA4

Mediator complex (MED) is an important auxiliary factor in the RNA polymerase II transcription apparatus, and MED13 is a subunit in the CDK8-kinase module of the complex. Currently, extensive clinical evidence has implicated its involvement in the pathogenesis of neurodevelopmental disorders (NDDs). However, the mechanism by which dysfunction of MED13 contributes to NDDs remains poorly understood. Here, we specifically knocked down Med13 expression in cortical neurons using in-utero electroporation to examine its function in cortical development and utilized mass spectrum to explore the downstream molecules involved in cortical development. We found that silencing Med13 in cortical neurons impaired its radial migration and contralateral projection as well as dendritic complexity in mice. Differential protein analysis of human neuroblastoma cells (SH-SY5Y) with MED13 deletion revealed a large number of dysregulated proteins, including PLXNA4. Notably, the impaired radial migration and callosal projection, but not dendritic complexity, were largely restored by overexpression of PlxnA4 in Med13 knock-down neurons. Collectively, our findings establish that Med13 regulates cortical neuronal radial migration and callosal projection at least in part through PlxnA4, shedding light on the molecular mechanisms underlying the pathogenesis of MED13-associated NDDs.