Regulation of Cortical Neurogenesis by MED13L via Transcriptional Priming and its Implications for MED13L Syndrome

MED13L is highly susceptible to neurodevelopmental disorders, yet the underlying developmental mechanisms remain poorly understood. We developed a gene knockout mouse model of MED13L syndrome to elucidate these mechanisms. Homozygous Med13l-null mice exhibit neonatal lethality and severe cortical neurogenesis deficits due to impaired differentiation of neural progenitors. In contrast, heterozygous Med13l-null mice are viable but display characteristic behavioral deficits of MED13L syndrome, including impaired learning and memory, reduced motor coordination, and heightened anxiety. Heterozygous mice also present with microcephaly and simplified neuronal morphology in the motor cortex. Conditional knockout of Med13l in the forebrain pyramidal lineage corroborated the motor and histological deficits observed. Proteomic, transcriptomic, and single-cell RNA sequencing analyses suggest that MED13L regulates cortical neurogenesis by priming developmental genes for transcriptional activation as a component of the mediator complex. These findings provide insights into the molecular and neurodevelopmental underpinnings of MED13L syndrome, paving the way for potential therapeutic strategies. To compare the gene expression profile of homozygous Med13l-null (KO), heterozygous (Het) and wild-type (WT) mice, we isolated total RNA from E13.5 embryonic cortex of 3 groups, with each group including 3 brain tissues. To compare the cell distribution of KO, Het and WT mice, we isolated the E13.5 embryonic cortical tissues and obtain 3 samples by pooling tissues from 5 individual embryos with the same genotype for each sample.MED13L综合征（MED13L syndrome）极易伴发神经发育障碍，但其潜在的发育机制仍有待深入解析。本研究构建了MED13L综合征的基因敲除小鼠模型，以阐明其背后的发育机制。纯合子Med13l敲除（Med13l-null）小鼠会出现新生期致死，并因神经前体细胞分化受损而表现出严重的皮层神经发生缺陷。与之相反，杂合子Med13l敲除小鼠可存活，但呈现MED13L综合征特有的行为学缺陷，包括学习记忆受损、运动协调能力下降以及焦虑水平升高。杂合子小鼠还会出现小头畸形，以及运动皮层神经元形态简化的表型。在前脑锥体神经元谱系中条件性敲除Med13l，验证了上述观察到的运动功能与组织学缺陷。蛋白质组学、转录组学以及单细胞RNA测序（single-cell RNA sequencing）分析显示，MED13L作为中介体复合物（mediator complex）的组分之一，通过启动发育基因的转录激活来调控皮层神经发生。本研究结果为阐明MED13L综合征的分子与神经发育机制提供了全新视角，也为潜在治疗策略的开发铺平了道路。为比较纯合子Med13l敲除（KO）、杂合子（Het）与野生型（WT）小鼠的基因表达谱，本研究从3组小鼠的E13.5胚胎皮层中提取总RNA，每组包含3份脑组织样本。为比较三组小鼠的细胞分布情况，本研究分离了E13.5胚胎皮层组织，并将相同基因型的5个个体胚胎的组织混合，制备得到3份样本。