Myocyte enhancer factor 2 C (MEF2C) is an important transcription factor during neurodevelopment. Mutation or deletion of MEF2C causes intellectual disability (ID) and common variants within MEF2C are associated with cognitive function and schizophrenia risk. We investigated if genes influenced by MEF2C during neurodevelopment are enriched for genes associated with neurodevelopmental phenotypes, and if this can be leveraged to identify biological mechanisms and individual brain cell types affected. We used a set of 1055 genes that were differentially expressed in the adult mouse brain following early embryonic deletion of Mef2c in excitatory cortical neurons. Using GWAS data, we found these differentially expressed genes (DEGs) to be enriched for genes associated with schizophrenia, intelligence and educational attainment but not autism spectrum disorder (ASD). For this gene-set, genes that overlap with target genes of the Fragile X mental retardation protein (FMRP) are a major driver of these enrichments. Using trios data, we found these DEGs to be enriched for genes containing de novo mutations reported in ASD and ID, but not schizophrenia. Using single cell RNA-seq data, we identified that a number of different excitatory glutamatergic neurons in the cortex were enriched for these DEGs including deep layer pyramidal cells and cells in the retrosplenial cortex, entorhinal cortex and subiculum, and these cell types are also enriched for FMRP target genes. The involvement of MEF2C and FMRP in synapse elimination suggests that disruption of this process in these cell types during neurodevelopment contributes to cognitive function and risk of neurodevelopmental disorders.

中文翻译：

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受 MEF2C 影响的基因通过影响多种皮质兴奋性神经元的基因表达变化而导致神经发育疾病。

肌细胞增强因子 2 C (MEF2C) 是神经发育过程中的重要转录因子。MEF2C的突变或缺失导致智力障碍 (ID)， MEF2C中的常见变异与认知功能和精神分裂症风险相关。我们研究了在神经发育过程中受 MEF2C 影响的基因是否富含与神经发育表型相关的基因，以及是否可以利用它来识别生物学机制和受影响的个体脑细胞类型。我们使用了一组 1055 个基因，这些基因在早期胚胎缺失Mef2c后在成年小鼠大脑中差异表达在兴奋性皮层神经元中。使用 GWAS 数据，我们发现这些差异表达基因 (DEG) 富含与精神分裂症、智力和教育程度相关的基因，但与自闭症谱系障碍 (ASD) 无关。对于这个基因组，与脆性 X 智力迟钝蛋白 (FMRP) 的靶基因重叠的基因是这些富集的主要驱动力。使用 trios 数据，我们发现这些 DEG 富含包含de novo的基因在 ASD 和 ID 中报告了突变，但在精神分裂症中没有。使用单细胞 RNA-seq 数据，我们发现皮质中许多不同的兴奋性谷氨酸能神经元富含这些 DEG，包括深层锥体细胞和脾后皮质、内嗅皮质和下托细胞，这些细胞类型也富集FMRP 靶基因。MEF2C 和 FMRP 在突触消除中的参与表明，在神经发育过程中这些细胞类型中这一过程的中断有助于认知功能和神经发育障碍的风险。