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：
9246340
负责人：
John James McMahon
金额：
$ 1.94万
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 2017-06-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9246340
关键词：
Ablation Address Alprostadil Apoptosis Apoptotic Attenuated Autistic Disorder Binding Biogenesis Brain Candidate Disease Gene Cells Cerebral cortex Clinical Complement Complex Cortical Malformation Data Deposition Development Disease Electroporation Embryo Epilepsy Etiology Event Exons Functional disorder Generations Genes Genetic Genetic Translation Genetic study Goals Human Genetics Image Impairment Intellectual functioning disability Knock-out Knowledge Link Mediator of activation protein Messenger RNA Microcephaly Molecular Mus Mutant Strains Mice Mutation Neurodevelopmental Disorder Neurons Pathogenesis Pathogenicity 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 experimental study in utero in vivo knock-down malformation mutant nerve stem cell nervous system disorder neurogenesis neuropathology overexpression progenitor public health relevance 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（由适用提供）：胚胎神经发生是一个严格控制的过程，大脑皮层开发。在神经发生过程中，神经基因源首先经历增生的分裂，从而引起祖细胞的一级。随着神经发生的进行，祖细胞逐渐引起神经元。对这种后代的平衡产生的破坏与皮质发育中的畸变有关，包括小头畸形（脑大小降低）。最近的人类遗传学研究表明，RNA结合外显子连接复合物（EJC）内部的突变在临床上与神经发育疾病相关，在某些情况下是小头畸形的。我们发现，小鼠EJC成分的单倍不足会导致小头畸形，并具有早熟的神经元产生和凋亡。 p53的遗传消融显着，尽管部分反应了小头畸形和神经发生表型。这种部分救援将p53作为疾病病理学的主要因素，但建议独立于p53的机制也有贡献。在此提案中，我们解决了两个关键问题：1）EJC障碍后激活p53的机制是什么，2）EJC的p53独立函数是什么，对小头畸形有助于p53。最近，我们已经确定核糖体生物发生在EJC突变小鼠中受到破坏，这一事件已被良好确定以引起p53反应。在此，直接测试核糖体生物发生受损的建议是p53激活的关键介体。此外，我们将破译EJC在调节脂肪确定剂mRNA的翻译中的作用，以调节p53的机制调节神经发生。