Dissecting the role of the exon junction complex in embryonic corticogenesis

 描述（由申请人提供）：胚胎神经发生是大脑皮层发育的一个严格控制的过程。在神经发生过程中，神经祖细胞首先进行增殖分裂，主要产生祖细胞。随着神经发生的进行，祖细胞分裂越来越多地产生神经元。这种后代平衡生产的中断与皮质发育的畸变有关，包括小头畸形（大脑尺寸减小）。最近的人类遗传学研究表明，RNA结合外显子连接复合物（EJC）的组成部分内的突变与神经发育障碍和某些情况下的小头畸形临床相关。我们发现，小鼠EJC组分的单倍不足导致小头畸形，并伴有早熟神经元产生和凋亡。基因消融p53显着，虽然部分，拯救小头畸形和神经发生表型。这种部分拯救暗示p53作为疾病病理学的主要贡献者，但表明p53独立机制也有贡献。在这个建议中，我们解决了两个关键问题：1）EJC损伤后激活p53的机制是什么？2）EJC的p53独立功能是什么？最近，我们已经确定，核糖体生物合成被破坏EJC突变小鼠，这是一个事件，这是建立了引发p53反应。在此，建议直接测试受损的核糖体生物合成是否作为p53激活的关键介质。此外，我们将破译EJC在调节命运决定因子mRNA的翻译中的作用，作为一种调节神经发生的p53非依赖性机制。

 DESCRIPTION (provided by applicant): Embryonic neurogenesis is a tightly controlled process through which the cerebral cortex develops. During neurogenesis neural progenitors first undergo proliferative divisions, giving rise primarily to progenitors. As neurogenesis proceeds progenitor divisions increasingly give rise to neurons. Disruptions to this balanced production of progeny are associated with aberrations in cortical development, including microcephaly (reduced brain size). Recent human genetics studies reveal that mutations within components of the RNA binding exon junction complex (EJC) are clinically associated with neurodevelopmental disorders and in some cases microcephaly. We find that haploinsufficiency of EJC components in mice results in microcephaly, with precocious neuron production and apoptosis. Genetic ablation of p53 significantly, albeit partially, rescues microcephaly and neurogenesis phenotypes. This partial rescue implicates p53 as a major contributor to disease pathology, but suggests p53-independent mechanism also contribute. In this proposal we address two key questions: 1) What is the mechanism activating p53 following EJC impairment and 2) What are the p53- independent functions of the EJC which contribute to microcephaly. Recently, we have identified that ribosome biogenesis is disrupted in EJC mutant mice, an event which is well established to elicit a p53 response. Herein, propose to directly test if impaired ribosome biogenesis acts as a key mediator of p53 activation. Additionally, we will decipher the role of the EJC in modulating translation of fate determinant mRNAs as a p53-independent mechanism regulating neurogenesis.