Analysis of the Exon Junction Complex in Neural Development and Microcephaly

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The objectives of this career development proposal are first to expand the Pi's training in neural development and second, to understand why mutation of an RNA-binding complex component causes reduced brain size. Towards the first objective we have formulated a career development plan to provide necessary scientific and career training for the PI to achieve success as an independent.investigator. For the K99 phase of the proposal, this training will occur at NHGRI on the NIH campus. Integral to this training is a panel of advisors that bring together expertise in mouse embryology, neural development, microcephaly, and mitosis. Towards the second objective we will explore a new mouse model of microcephaly we have identified called Mos2. Microcephaly is a genetic disorder in which brain size is significantly reduced resulting in mental retardation. It has been proposed that microcephaly is caused by defects in neural stem cell division in the developing neocortex. There is a need for additional models to further validate this concept. Our initial characterization of Mos2 mutants indicates that neural stem cell function is compromised in these mice due to mutation in a component of the exon junction complex, an RNA-binding complex not previously implicated in neural development. In this proposal we will test the hypothesis that this complex is required for neural stem cell maintenance by regulating asymmetric cell division. First we will characterize the neural stem cell and differentiated neuronal populations in Mos2 mutants to evaluate how neural stem cell function is disrupted. Second we will use cell biological and genetic approaches to ask if other components of the exon exon junction complex regulate brain size. Third, we will use RNAi to test the hypothesis that this complex is required for cell division. This proposal will provide insight into regulation of neural development, the mechanism of microcephaly and other neurodevelopmental diseases, and specifically address the role of RNA binding proteins in these processes. Pursuing these aims-will provide the necessary foundation for a career as an independent investigator in neural development.