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Essential requirements of Eif4a3 in brain development and disease

Eif4a3 在大脑发育和疾病中的基本需求

基本信息

批准号：
10178122
负责人：
Debra Silver
金额：
$ 34.55万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10178122
关键词：
Address Binding Biological Assay Brain Brain Pathology Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex Copy Number Polymorphism Corpus Callosum Coupled Data Set Defect Development Diagnostic Disease Etiology Exhibits Exons Funding Genes Genetic Genomics Goals Grant Human Image Impairment In Vitro Intellectual functioning disability Measures Mediating Microcephaly Microtubules Mitosis Molecular Mus Mutant Strains Mice Mutate Mutation Neurodevelopmental Disorder Neurons Newborn Infant Pathology Patients Phenotype Positioning Attribute Process RNA RNA Binding Radial Regulation Role Sedimentation process Sum Syndrome Testing Therapeutic Transcript autism spectrum disorder base cognitive disability craniofacial excitatory neuron fetal genetic analysis imaging modality in vivo induced pluripotent stem cell insight mouse model mutant nerve stem cell nervous system disorder neurodevelopment neurogenesis neuron development neuroregulation novel progenitor stem cell model tool transcriptome unpublished works

项目摘要

Abstract Eif4a3 is a component of an RNA binding exon junction complex (EJC) implicated in neural development and disease. The EJC is composed of Eif4a3, Magoh, and Rbm8a. EIF4A3 mutations are associated with intellectual disability and hypomorphic mutations cause Richieri-Costa-Pereira syndrome (RCPS), a craniofacial developmental syndrome accompanied by microcephaly and cognitive disability. Yet, the underlying mechanisms of EIF4A3-mediated neurodevelopmental pathologies remain largely unknown. This renewal proposal aims to address this gap by defining requirements for Eif4a3 in two critical processes of cortical development: neurogenesis and neuronal maturation. In the prior funding period of this grant, we discovered that Magoh mutant progenitors exhibit prolonged mitosis, which directly alters fates of newborn progeny. We generated mouse models for all 3 core EJC components. Using these mice we discovered that EJC haploinsufficiency in progenitors results in strikingly similar defects in neurogenesis, microcephaly, and dysregulation of common transcripts. Our genetic and genomic discoveries indicate that Eif4a3 may control neural progenitors and neurogenesis via the EJC. In contrast, our recent unpublished work indicate that, Eif4a3 may have EJC-independent functions in neurons. Further, we implicate microtubule regulation in these non- canonical mechanisms. Based on our findings we hypothesize that Eif4a3 employs canonical RNA regulatory and non-canonical microtubule mechanisms to differentially control progenitors and neurons during brain development. This proposal will test this hypothesis by exploiting unique mouse models and human iPSC models, as well as live imaging assays developed in our lab. We will: (1) define cellular and molecular mechanisms by which Eif4a3 influences neurogenesis, (2) determine developmental and molecular requirements of Eif4a3 in neuronal maturation, and (3) determine the cellular and molecular impact of EIF4A3 mutations in human cells. Successfully completed, we will have significantly advanced our understanding of how Eif4a3 controls critical stages of cortical development, via both canonical and non-canonical mechanisms. We anticipate the discoveries resulting from this proposal will be broadly impactful for understanding cortical development and the etiology of neurodevelopmental disease.

抽象的 Eif4a3 是 RNA 结合外显子连接复合物 (EJC) 的一个组成部分，与神经发育和疾病。 EJC 由 Eif4a3、Magoh 和 Rbm8a 组成。 EIF4A3突变与智力相关残疾和低等位基因突变会导致 Richieri-Costa-Pereira 综合征 (RCPS)，这是一种颅面部疾病伴有小头畸形和认知障碍的发育综合征。然而，底层 EIF4A3 介导的神经发育病理机制仍然很大程度上未知。此次续订该提案旨在通过在皮质的两个关键过程中定义 Eif4a3 的要求来解决这一差距发育：神经发生和神经元成熟。在本次资助的前期资助期间，我们发现 Magoh 突变祖细胞表现出延长的有丝分裂，这直接改变新生后代的命运。我们为所有 3 个核心 EJC 组件生成鼠标模型。使用这些小鼠我们发现 EJC 祖细胞的单倍体不足导致神经发生、小头畸形和神经发生方面惊人相似的缺陷常见转录本的失调。我们的遗传和基因组发现表明 Eif4a3 可能控制通过 EJC 进行神经祖细胞和神经发生。相比之下，我们最近未发表的工作表明，Eif4a3 神经元中可能具有独立于 EJC 的功能。此外，我们将微管调节与这些非规范机制。根据我们的发现，我们假设 Eif4a3 采用规范的 RNA 调控和非经典微管机制在大脑过程中差异控制祖细胞和神经元发展。该提案将通过利用独特的小鼠模型和人类 iPSC 来测试这一假设模型以及我们实验室开发的实时成像分析。我们将：（1）定义细胞和分子 Eif4a3 影响神经发生的机制，(2) 决定发育和分子 Eif4a3 在神经元成熟中的要求，以及 (3) 确定 EIF4A3 的细胞和分子影响人类细胞的突变。如果成功完成，我们将显着提高我们对如何 Eif4a3 通过规范和非规范机制控制皮质发育的关键阶段。我们预计该提案的发现将对理解皮质产生广泛影响神经发育疾病的发育和病因学。