Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II
Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II
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DOI：
10.4161/cc.5.3.2412
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发表时间：
2006-02-01
期刊：
影响因子：
4.3
通讯作者：
Hirano, T
中科院分区：
文献类型：
--
作者：
Trimborn, M;Schindler, D;Hirano, T
常染色体隐性遗传性原发性小头畸形(MCPH)是一种以脑体积显著缩小和智力低下为特征的神经发育障碍。编码小脑磷脂的MCPH1基因突变导致MCPH和一种独特的细胞表型，染色体在G(2)早期过早凝聚，有丝分裂后延迟解聚。在这里，我们发现在MCPH1患者细胞中，siRNA介导的凝聚素II亚单位的耗尽导致细胞显著减少，细胞周期的G(1)和G(2)期都有凝聚缺陷。当HeLa细胞中的小脑磷脂和凝聚素II同时被耗尽时，也得到了类似的结果。相反，凝聚素I亚基的缺失并不能逆转细胞的表型。在MCPH1患者的前期样细胞中，凝聚素I一直停留在细胞质中。我们的结果为MCPH1缺乏症的异常染色体凝聚提供了分子解释，并为凝聚素I和凝聚素II受不同途径调控提供了额外的证据。
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by marked reduction in brain size and mental retardation. Mutations in the gene MCPH1, encoding microcephalin, cause MCPH and a unique cellular phenotype with premature chromosome condensation in early G(2) phase and delayed decondensation post mitosis. Here, we show that in MCPH1 patient cells, siRNA-mediated depletions of condensin II subunits lead to a pronounced reduction of cells with the condensation defects in both G(1) and G(2) phases of the cell cycle. Similar results are obtained when microcephalin and condensin II are simultaneously depleted in HeLa cells. In contrast, depletions of condensin I subunits do not reverse the cellular phenotype. Consistently, condensin I stays in the cytoplasm in the prophase-like cells of MCPH1 patients. Our results offer a molecular explanation for the aberrant chromosome condensation in MCPH1-deficiency and provide additional evidence that condensin I and II are regulated by distinct pathways.