Regulation of cortical neurogenesis by MED13L via transcriptional priming and its implications for MED13L syndrome

Pathogenic variants in MED13L cause MED13L syndrome, a well-defined neurodevelopmental disorder characterized by motor deficits, intellectual disability, and language delay, yet its underlying developmental and molecular mechanisms remain largely elusive. To address this gap, we generated a gene knockout mouse model of MED13L syndrome. While homozygous Med13l knockout exhibit neonatal lethality accompanied by reduced brain volume and cortical thickness, heterozygous mice are viable and display hallmarks of MED13L syndrome, including impaired learning and memory, reduced motor coordination, and heightened anxiety. Additionally, heterozygous mice show microcephaly with simplified neuronal morphology in the motor cortex. Single-cell transcriptomics and immunofluorescence reveal severe cortical neurogenesis deficits in Med13l knockout embryos, driven by impaired neural progenitor differentiation. Integrative multi-omics analyses reveal that MED13L orchestrates cortical neurogenesis by priming the transcriptional activation of key developmental genes, including Neurod2, Sox5, Auts2, and Nfib. This priming effect is mediated by MED13L binding to the core mediator complex, which facilitates the complex's association with RNA Pol II and subsequent dissociation from MED13L. These findings uncover a pivotal role for MED13L in transcriptional regulation during brain development and highlight potential targets for restoring normal transcriptional programs in MED13L syndrome. Modeling Med13l deficiency in mice reveals that MED13L shapes cortical neurogenesis through a transcriptional priming effect on key developmental genes, offering mechanistic insight and potential therapeutic targets for MED13L syndrome.