Essential requirements of Eif4a3 in brain development and disease

摘要 Eif 4a 3是参与神经发育的RNA结合外显子连接复合物（EJC）的组分， 疾病EJC由Eif 4a 3、Magoh和Rbm 8a组成。EIF 4A 3突变与智力相关 残疾和亚形态突变导致Richieri-Costa-佩雷拉综合征（RCPS），一种颅面 伴有小头畸形和认知障碍的发育综合征。然而， EIF 4A 3介导的神经发育病理学的机制在很大程度上仍然未知。此续订 一项提案旨在通过定义Eif 4a 3在两个关键的皮层过程中的要求来解决这一差距。 发育：神经发生和神经元成熟。在此资助的前一个资助期，我们发现， Magoh突变体祖细胞表现出延长的有丝分裂，这直接改变了新生后代的命运。我们 为所有3个核心EJC组件生成小鼠模型。利用这些小鼠，我们发现EJC 祖细胞的单倍不足导致神经发生、小头畸形和 常见转录本的失调。我们的遗传和基因组发现表明Eif 4a 3可能控制着 神经祖细胞和神经发生。相反，我们最近未发表的工作表明，Eif 4a 3 可能在神经元中具有EJC独立的功能。此外，我们暗示微管调节在这些非- 规范机制基于我们的研究结果，我们假设Eif 4a 3采用典型的RNA调控机制， 和非典型微管机制，以区别控制祖细胞和神经元在脑 发展该提案将通过利用独特的小鼠模型和人类iPSC来验证这一假设 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 Eif 4a 3影响神经发生的机制，（2）决定发育和分子水平 EIF 4a 3在神经元成熟中的需求，以及（3）确定EIF 4a 3的细胞和分子影响 人类细胞的突变。成功完成，我们将大大提高我们的理解， Eif 4a 3通过规范和非规范机制控制皮质发育的关键阶段。我们 预计这项提议所带来的发现将对理解大脑皮层产生广泛的影响。 发展和神经发育疾病的病因学。

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 In contrast, our recent unpublished work indicate that, Eif4a3 may have EJC-independent functions in neurons.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.