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Abstract：
MCPH1 has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of Mcph1 in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of Mcph1 resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as Satb2 and Cdkn1c, was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized Mcph1 knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in Mcph1 knockout MEFs, and silencing p19Arf restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly.
摘要：
MCPH1已被确定为原发性小头畸形1型的致病基因，这是一种神经发育障碍，其特征是大脑尺寸减小和生长延迟。作为一种多功能蛋白质,据报道，MCPH1抑制TERT的表达并与转录调节因子E2F1相互作用。然而,目前尚不清楚MCPH1是否通过其转录调节功能调节大脑发育。这项研究表明，小鼠中Mcph1的敲除早在胚胎阶段E11.5就导致生长延迟。转录组分析（RNA-seq）显示，Mcph1的缺失导致有限数量基因的表达水平发生变化。虽然E2F1的一些表达靶点，例如Satb2和Cdkn1c，受到影响,差异表达基因(DEGs)作为E2F1靶基因没有显著富集。进一步的研究表明，原代和永生化的Mcph1敲除小鼠胚胎成纤维细胞（MEFs）表现出细胞周期停滞和细胞衰老表型。有趣的是,在Mcph1敲除MEF中检测到p19ARF的上调，沉默p19Arf可将细胞周期和生长停滞恢复到野生型水平。我们的研究结果表明，MCPH1不太可能通过E2F1介导的转录调节来调节神经发育。p19ARF依赖性细胞周期停滞和细胞衰老可能导致原发性小头畸形中观察到的发育异常。
