小颅畸形相关蛋白WDR62调控大脑发育的分子机制研究

Human autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder hallmarked by significantly reduced brain size and variable intellectual disability.Mutation of WD40-repeat protein 62(WDR62) has been recognized as the second major cause of MCPH and we have reported recently that WDR62 regulates the maintenance of neural progenitor cells (NPCs) during cortical development through JNK1(Xu et al., Cell Reports 2014).However, the detailed biological function of WDR62 and the underlying mechanism by which WDR62 regulates JNK signaling are still not very clear. Here, we generate WDR62 deficient mice which exhibit reduced brain size. Through biochemical study and shRNA screening,we demonstrate that WDR62 organize a novel protein complex including WDR62,POSH, MEKK3, MKKs and JNK1. POSH, MEKK3, WDR62 and JNK1 depletion or deficiency phenocopy each other in defects including premature differentiation of NPCs. Together with WDR62 and other gene knockout mice models, we will explore the role of WDR62 and the new complex in brain development and try to provide an insight into the molecular mechanisms underlying MCPH pathogenesis.

最近3年的研究表明WDR62基因突变与小颅畸形症（microcephaly, MCPH）和智力低下密切相关，并且是造成MCPH的第二大主因。虽然我组最近发现WDR62通过JNK1调控神经干细胞的自我更新与分化，但是，有关WDR62在大脑发育过程中的生理功能和作用机制，以及WDR62突变如何导致小颅畸形症的具体致病机制目前还不是很清楚。我们通过生化和shRNA筛选手段，发现WDR62作为支架蛋白参与组织和调控一个新的JNK信号通路蛋白复合体。初步研究表明，该复合体的不同成员包括WDR62, POSH, MEKK3, MKKs和JNK1/2等均参与大脑神经干细胞发育的调控，包括神经干细胞的自我更新与分化及神经迁移。我们制备了5种相关的小鼠动物模型，将深入研究WDR62及相关复合体在大脑发育中的作用与相关的生理和病理机制，从而促进对MCPH发病机理的了解并为MCPH的治疗提供理论依据。

WDR62）的遗传缺失突变在不同的智力低下家系中被发现，并被认为是小头畸形和智力低下致病相关基因。我们最近通过生化和shRNA筛选手段发现WDR62作为支架蛋白，可能参与组织和调控一个新的JNK信号通路蛋白复合体。初步研究表明，该复合体的不同成员，包括WDR62，POSH, MEKK3, MKKs和JNK1/2等均参与大脑神经干细胞发育的调控。我们将前期研究基础上，进一步在体内研究WDR62在大脑发育过程中确切的生理功能，通过生化手段发掘新的与大脑发育相关的JNK信号通路蛋白复合体，探索不同的智力低下致病相关基因在大脑发育中相关的分子细胞学机制。我们制备5种不同的小鼠动物模型，深入研究WDR62基因在大脑发育过程中的作用与相关的生理和病理机制，从而进一步促进对小头畸形发病机理的了解，同时，我们还在寨卡病毒导致小头畸形的发病机制研究中取得许多国际关注的成绩。这些研究为小头畸形的治疗提供动物模型及理论依据。

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