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 In contrast, our recent unpublished work indicate that, Eif4a3 may have EJC-independent functions in neurons.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.
This project will advance our understanding of neural progenitor fate specification and neuronal maturation during brain development. It will further an understanding of the etiology of neurodevelopmental disorders, including intellectual disability, microcephaly, and autism. Therefore, this study may eventually help in the development of diagnostic and therapeutic options for broad neurological disorders.
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