Huntingtin Is Required for Mitotic Spindle Orientation and Mammalian Neurogenesis
Huntingtin Is Required for Mitotic Spindle Orientation and Mammalian Neurogenesis
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DOI：
10.1016/j.neuron.2010.06.027
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发表时间：
2010-08-12
期刊：
影响因子：
16.2
通讯作者：
Humbert, Sandrine
中科院分区：
文献类型：
--
作者：
Godin, Juliette D.;Colombo, Kelly;Humbert, Sandrine
亨廷顿蛋白是亨廷顿病中突变的蛋白质，亨廷顿病是一种毁灭性的神经退行性疾病。我们在这里证明亨廷顿蛋白对于控制有丝分裂至关重要。有丝分裂期间亨廷顿蛋白定位于纺锤体极。 RNAi 介导的细胞内亨廷顿蛋白沉默通过使动力蛋白、动力蛋白和大核有丝分裂装置 NuMA 蛋白的 p150(Glued) 亚基错误定位而破坏纺锤体方向。这导致贴壁细胞体外有丝分裂后细胞凋亡增加。通过 RNAi 或 Hdh 基因消融体内亨廷顿蛋白失活会影响小鼠胚胎心室区皮层祖细胞的纺锤体方向和细胞命运。这一功能在果蝇中是保守的，神经母细胞前体中果蝇亨廷顿蛋白的特异性破坏导致纺锤体定向错误。此外，果蝇亨廷顿蛋白可以恢复哺乳动物细胞中纺锤体的定向错误。这些发现揭示了亨廷顿蛋白在细胞分裂中的意想不到的作用，对健康和疾病具有潜在的重要影响。
Huntingtin is the protein mutated in Huntington's disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease.