Cdk5rap2 Interacts with Pericentrin to Maintain the Neural Progenitor Pool in the Developing Neocortex
Cdk5rap2 Interacts with Pericentrin to Maintain the Neural Progenitor Pool in the Developing Neocortex
复制标题
Cdk5rap2 与 Pericentrin 相互作用以维持发育中神经皮层的神经祖细胞库
DOI：
10.1016/j.neuron.2010.03.036
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发表时间：
2010-05-13
期刊：
影响因子：
16.2
通讯作者：
Tsai, Li-Huei
中科院分区：
文献类型：
--
作者：
Buchman, Joshua J.;Tseng, Huan-Chung;Tsai, Li-Huei
原发性常染色体隐性小头畸形（MCPH）和Majewski骨发育异常原始性侏儒症II型（MOPDII）都是导致出生时脑体积减小的遗传性疾病。MCPH被认为是由神经祖细胞池大小的改变引起的，但这种缺陷的原因尚未被彻底探索。我们发现与MCPH相关的基因之一Cdk5rap2在神经祖细胞池中高度表达，其缺失导致顶端祖细胞耗竭和细胞周期退出增加，从而导致过早的神经元分化。我们将Cdk5rap2的功能与中心周围物质蛋白中心周围蛋白联系起来，中心周围蛋白的功能丧失与MOPDII有关。神经祖细胞中心周蛋白的缺失表现了Cdk5rap2敲低的效应，并导致Cdk5rap2向中心体募集的减少。我们的发现揭示了一个共同的机制，涉及神经发生程序的畸变，这可能是多种疾病中小头畸形发展的基础。
Primary autosomal-recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism type II (MOPDII) are both genetic diseases that result in decreased brain size at birth. MCPH is thought to arise from alterations in the size of the neural progenitor pool, but the cause of this defect has not been thoroughly explored. We find that one of the genes associated with MCPH, Cdk5rap2, is highly expressed in the neural progenitor pool and that its loss results in a depletion of apical progenitors and increased cell-cycle exit leading to premature neuronal differentiation. We link Cdk5rap2 function to the pericentriolar material protein pericentrin, loss of function of which is associated with MOPDII. Depletion of pericentrin in neural progenitors phenocopies effects of Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome. Our findings uncover a common mechanism, involving aberrations in the neurogenesis program, that may underlie the development of microcephaly in multiple diseases.