MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway
MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway
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DOI：
10.1038/ncb2342
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发表时间：
2011-11-01
影响因子：
21.3
通讯作者：
Wang, Zhao-Qi
中科院分区：
文献类型：
--
作者：
Gruber, Ralph;Zhou, Zhongwei;Wang, Zhao-Qi
原发性小头畸形1是由MCPH 1基因突变引起的神经发育障碍，其产物MCPH 1（也称为小脑磷脂和BRIT 1）调节DNA损伤反应。在这里，我们表明，在小鼠中的Mcph 1中断的结果在原发性小头畸形，模仿人类MCPH 1的症状，由于过早切换的神经祖细胞从对称到不对称分裂。MCPH 1缺陷会消除Chk 1在中心体的定位，导致Cdk 1过早激活和有丝分裂早期进入，从而使有丝分裂和中心体周期解偶联。这使有丝分裂纺锤体排列方向错误，并使神经祖细胞的分裂平面移位，从而使神经源性细胞的命运偏向。沉默Cdc 25 b，Chk 1的中心体底物，纠正MCPH 1缺陷诱导的纺锤体错位，并挽救Mcph 1敲除新皮层中过早的神经原性生产。因此，MCPH 1通过其在Chk 1-Cdc 25-Cdk 1通路中的功能将中心体周期与有丝分裂偶联，是精确的有丝分裂纺锤体方向所需的，从而调节祖细胞分裂模式以维持脑大小。
Primary microcephaly 1 is a neurodevelopmental disorder caused by mutations in the MCPH1 gene, whose product MCPH1 (also known as microcephalin and BRIT1) regulates DNA-damage response. Here we show that Mcph1 disruption in mice results in primary microcephaly, mimicking human MCPH1 symptoms, owing to a premature switching of neuroprogenitors form symmetric to asymmetric division. MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle. This misorients the mitotic spindle alignment and shifts the division plane of neuroprogenitors, to bias neurogenic cell fate. Silencing Cdc25b, a centrosome substrate of Chk1, corrects MCPH1-deficiency-induced spindle misalignment and rescues the premature neurogenic production in Mcph1-knockout neocortex. Thus, MCPH1, through its function in the Chk1-Cdc25-Cdk1 pathway to couple the centrsome cycle with mitosis, is required for precise mitotic spindle orientation and thereby regulates the progenitor division mode to maintain brain size.