Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.
Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.
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DOI：
10.1038/srep43708
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发表时间：
2017-03-08
影响因子：
4.6
通讯作者：
Louvi A
中科院分区：
文献类型：
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作者：
Sgourdou P;Mishra-Gorur K;Saotome I;Henagariu O;Tuysuz B;Campos C;Ishigame K;Giannikou K;Quon JL;Sestan N;Caglayan AO;Gunel M;Louvi A
WD重复结构域62 （WDR62）的隐性突变导致小头畸形和广泛的严重脑畸形。小鼠同源性的破坏导致小头畸形，其基础是在神经发生晚期新皮质祖细胞增殖减少，不对称中心体遗传异常导致神经元迁移延迟，以及神经元分化改变。WDR62的纺锤极定位和有丝分裂进程在患者来源的成纤维细胞中是有缺陷的，与小鼠新皮质祖细胞类似，在早期中期短暂停止。WDR62的表达与染色体客运复合体（CPC）的组分密切相关，CPC是有丝分裂的关键调节因子。野生型WDR62，而不是疾病相关突变型，与CPC核心酶极光激酶B相互作用，并且在患者来源的成纤维细胞中，着丝粒上CPC成分的染色发生改变。我们的研究结果证明了WDR62在新皮质发育中的关键和多样化功能，并提供了对其破坏导致大量结构异常的机制的见解。
Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.