Inhibition of Autism-Related Crm1 Disrupts Mitosis and Induces Apoptosis of the Cortical Neural Progenitors
Inhibition of Autism-Related Crm1 Disrupts Mitosis and Induces Apoptosis of the Cortical Neural Progenitors
复制标题
抑制自闭症相关的 Crm1 会破坏有丝分裂并诱导皮质神经祖细胞凋亡
DOI：
10.1093/cercor/bhaa011
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Jie-Guang Chen
中科院分区：
文献类型：
--
作者：
Xue Li;Yue Feng;Meifang Yan;Xiaomeng Tu;Bin Xie;Fangfang Ni;Chunsheng Qu;Jie-Guang Chen
染色体2 p15 -16.1的从头微缺失呈现临床可识别的表型，包括精神发育迟滞、孤独症和小头畸形。染色体维持1（CRM 1）是.2p15 -16.1微缺失患者中常见的缺失基因，也是最小缺失病例中发现的两个基因之一。本研究通过抑制Crm 1蛋白或敲除Crm 1基因，探讨Crm 1在小鼠脑发育中的作用及其机制。Crm 1的抑制降低了皮质神经祖细胞的增殖并增加了p53依赖的凋亡，从而阻碍了胚胎大脑皮质的生长。离体胚胎脑切片中有丝分裂的实时成像揭示，CRM 1的抑制使皮质祖细胞在中期停止。停滞的细胞最终进入假G1期，没有染色体分离。有丝分裂滑移细胞以纺锤体组装检查点（SAC）的持续表达为标志，抑制SAC可挽救细胞免于凋亡。我们的研究表明，激活SAC和诱导有丝分裂滑移可能导致皮质神经前体细胞凋亡。由此导致的细胞死亡很可能导致与CRM 1相关的染色体2 p15 -16.1微缺失相关的小头畸形。
De novo microdeletion of chromosome 2p15–16.1 presents clinically recognizable phenotypes that include mental.retardation, autism, and microcephaly. Chromosomal maintenance 1 (CRM1) is a gene commonly missing in patients with.2p15–16.1 microdeletion and one of two genes found in the smallest deletion case. In this study, we investigate the role and.mechanism of Crm1 in the developing mouse brain by inhibiting the protein or knocking down the gene in vivo. Inhibition.of Crm1 reduces the proliferation and increases p53-dependent apoptosis of the cortical neural progenitors, thereby.impeding the growth of embryonic cerebral cortex. Live imaging of mitosis in ex vivo embryonic brain slices reveals that.inhibition of CRM1 arrests the cortical progenitors at metaphase. The arrested cells eventually slip into a pseudo-G1 phase.without chromosome segregation. The mitotic slippage cells are marked by persistent expression of the spindle assembly.checkpoint (SAC), repressing of which rescues the cells from apoptosis. Our study reveals that activating the SAC and.inducing the mitotic slippage may lead to apoptosis of the cortical neural progenitors. The resulting cell death may well.contribute to microcephaly associated with microdeletion of chromosome 2p15–16.1 involving CRM1.