Dissecting the role of the exon junction complex in embryonic corticogenesis

剖析外显子连接复合物在胚胎皮质发生中的作用

基本信息

批准号：
9123054
负责人：
John James McMahon
金额：
$ 5.8万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123054
关键词：
Ablation Address Affect Alprostadil Apoptosis Apoptotic Attenuated Autistic Disorder Binding Biogenesis Brain Candidate Disease Gene Cells Cerebral cortex Complement Complex Cortical Malformation Data Deposition Development Disease Electroporation Embryo Epilepsy Equilibrium Etiology Event Exons Functional disorder Generations Genes Genetic Genetic Translation Genetic study Goals Human Genetics Image Impairment Intellectual functioning disability Knock-out Knowledge Life Link Mediator of activation protein Messenger RNA Microcephaly Molecular Mus Mutant Strains Mice Mutation Neurodevelopmental Disorder Neurons Pathogenesis Pathology Phenotype Play Process Production Proliferating RNA RNA Binding RNA Splicing Regulation Repression Research Ribosomal Interaction Ribosomal Proteins Ribosomes Role Symptoms TP53 gene Testing Transcript Translational Regulation Translations attenuation brain size in utero in vivo knock-down malformation mutant nerve stem cell nervous system disorder neurogenesis neuropathology overexpression progenitor public health relevance research study response targeted treatment transcriptome sequencing

项目摘要

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.

描述（由申请人提供）：胚胎神经发生是大脑皮层发育的严格控制过程，在神经发生过程中，神经祖细胞首先经历增殖分裂，主要产生祖细胞。随着神经发生的进行，祖细胞分裂逐渐产生神经元。后代的平衡生产与皮质发育异常有关，包括小头畸形（大脑尺寸减小）。最近的人类遗传学研究表明，组件内的突变。 RNA 结合外显子连接复合物 (EJC) 的缺失在临床上与神经发育障碍有关，在某些情况下，我们发现小鼠中 EJC 成分的单倍体不足会导致小头畸形，并导致 p53 的早熟神经元产生和细胞凋亡。，挽救小头畸形和神经发生表型，这种部分挽救表明 p53 是疾病病理学的主要贡献者，但表明 p53 独立机制也有贡献。在这个提案中，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，导致小头畸形。最近，我们发现 EJC 突变体中核糖体生物发生被破坏。小鼠，这是一个已被证实可以引发 p53 反应的事件，在此，我们建议直接测试受损的核糖体生物发生是否充当 p53 激活的关键介质。 EJC 在调节命运决定子 mRNA 翻译中的作用作为调节神经发生的 p53 独立机制。