Expression profiling analysis of mouse E10.5 Magoh mutant brain cortices

Human brain structure and size requires regulated division of neural stem cells (NSCs). NSCs undergo precise divisions to self-renew and to produce intermediate neural progenitors (INPs) and neurons. The factors that regulate NSC divisions remain poorly understood, as do mechanistic explanations of how aberrant NSC division causes reduced brain size, as seen in microcephaly. Here we demonstrate that Magoh, a component of the core exon junction complex (EJC) that binds spliced RNA, controls cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly due to INP depletion, neuronal apoptosis, and improper mitotic spindle orientation. Defective mitosis underlies these phenotypes as depletion of EJC components disrupts mitotic spindle integrity, chromosome number and genomic stability. We show that an essential function of Magoh is to regulate expression of the human microcephaly protein, LIS1, and that Lis1 addition rescues neurogenesis defects caused by Magoh knockdown, thus providing a genetic explanation for the microcephaly. This study uncovers new requirements for the EJC in brain development, NSC maintenance, mitosis and chromosome stability, thus implicating this complex in the pathogenesis of microcephaly. Mouse embryonic cortices were used for expression analysis 5 biological replicates each of control (C57BL/6) and Magoh mutant brains were analyzed人类大脑的结构与尺寸需要神经干细胞（neural stem cells, NSCs）进行受调控的分裂。神经干细胞需通过精准的分裂实现自我更新，并产生中间神经前体细胞（intermediate neural progenitors, INPs）与神经元。目前，调控神经干细胞分裂的相关因子仍未得到充分阐明，而异常神经干细胞分裂如何导致小头畸形中观察到的大脑尺寸减小的机制解释亦尚不清晰。本研究证实，结合剪接RNA的核心外显子连接复合物（exon junction complex, EJC）组分之一Magoh，可通过调控神经干细胞分裂来控制大脑皮层体积。Magoh单倍体剂量不足会因中间神经前体细胞耗竭、神经元凋亡以及有丝分裂纺锤体定向异常引发小头畸形。存在缺陷的有丝分裂是上述表型的基础：外显子连接复合物组分的敲除会破坏有丝分裂纺锤体完整性、染色体数目与基因组稳定性。本研究表明，Magoh的一项核心功能是调控人类小头畸形相关蛋白LIS1的表达，而补充Lis1可挽救Magoh敲低所导致的神经发生缺陷，从而为小头畸形提供了遗传学解释。本研究揭示了外显子连接复合物在大脑发育、神经干细胞维持、有丝分裂以及染色体稳定性中的新功能需求，进而暗示该复合物参与小头畸形的发病机制。本研究使用小鼠胚胎皮层开展表达分析，对对照组（C57BL/6）与Magoh突变型大脑各5个生物学重复样本进行了检测。