Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration
Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration
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DOI：
10.1093/hmg/ddi339
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Hirotsune, S
中科院分区：
文献类型：
--
作者：
Toyo-Oka, K;Sasaki, S;Hirotsune, S
在人类神经元迁移缺陷的无脑组织中，Lis1基因发生突变，并与NDEL1(以前称为Nudel)一起参与神经元发育过程中胞浆动力蛋白功能的调节。Ndel1的靶向破坏表明NDEL1可能有其他分子靶点来调节微管组织，以实现适当的神经元迁移。为了进一步了解Lis1和无脑畸形的分子机制，我们确定katanin p60微管切断蛋白是NDEL1的一个额外的分子靶点。我们证明了CDK5对NDEL1的磷酸化促进了NDEL1与p60之间的相互作用，表明P-NDEL1调节katanin p60的分布。Ndel1缺失突变体细胞核中p60的异常积聚支持NDEL1在p60调控中的重要作用。在迁移的神经元中，NDEL1的完全缺失或p60的显性负性突变体的表达导致了迁移缺陷和核-中心体距离的延长。我们的结果表明，NDEL1对有丝分裂细胞的分裂和神经元的迁移是必不可少的，不仅通过调节细胞质动力蛋白功能，而且通过调节katanin p60的定位和功能。
LIS1 is mutated in the human neuronal migration defect lissencephaly and along with NDEL1 (formerly NUDEL) participates in the regulation of cytoplasmic dynein function during neuronal development. Targeted disruption of Ndel1 suggested that NDEL1 could have other molecular targets that regulate microtubule organization for proper neuronal migration. To further understanding the molecular mechanism of LIS1 and lissencephaly, we identified the katanin p60 microtubule-severing protein as an additional molecular target of NDEL1. We demonstrate that phosphorylation of NDEL1 by Cdk5 facilitates interaction between NDEL1 and p60, suggesting that P-NDEL1 regulates the distribution of katanin p60. Abnormal accumulation of p60 in nucleus of Ndel1 null mutants supports an essential role of NDEL1 in p60 regulation. Complete loss of NDEL1 or expression of dominant negative mutants of p60 in migrating neurons results in defective migration and elongation of nuclear-centrosomal distance. Our results suggest that NDEL1 is essential for mitotic cell division and neuronal migration not only via regulation of cytoplasmic dynein function but also by modulation of katanin p60 localization and function.