Dissecting the role of the exon junction complex in embryonic corticogenesis

 描述(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，神经前体细胞首先经历增殖分裂，主要产生神经前体细胞。随着神经发生的进行，祖细胞分裂越来越多地产生神经元。破坏后代的这种平衡生产与皮质发育中的异常有关，包括小头畸形(大脑尺寸缩小)。最近的人类遗传学研究表明，RNA结合外显子连接复合体(EJC)组件内的突变在临床上与神经发育障碍有关，在某些情况下与小头畸形有关。我们发现，在小鼠中，EJC成分的单倍性不足会导致小头畸形，并伴有早熟神经元的产生和细胞凋亡。P53的基因消融显著地，尽管是部分地，挽救了小头畸形和神经再生的表型。这种部分挽救表明P53是疾病病理的主要贡献者，但也表明P53独立的机制也起到了作用。在这项建议中，我们解决了两个关键问题：1)在EJC损伤后激活P53的机制是什么；2)什么是EjC的P53独立功能，这些功能有助于小头畸形的发生。最近，我们已经发现在EJC突变小鼠中，核糖体的生物发生受到干扰，这一事件被公认为可以引发P53反应。在这里，建议直接测试受损的核糖体生物发生是否作为P53激活的关键中介。此外，我们将破译EJC在调节命运决定基因mRNAs翻译中的作用，作为一种独立于p53的调节神经发生的机制。

 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.