Analysis of the Exon Junction Complex in Neural Development and Microcephaly

这份职业发展提案的目标首先是扩大Pi在神经方面的培训 第二，了解为什么RNA结合复合物成分的突变会导致 大脑体积缩小。为了实现第一个目标，我们制定了职业发展计划， 为主要研究者提供必要的科学和职业培训，以作为独立研究者取得成功。的 K99阶段的培训在NIH校园的NHGRI进行。在建议的原产地标准阶段， 研究将在杜克大学医学中心进行。这项培训的组成部分是一个顾问小组， 汇集了小鼠胚胎学、神经发育、小头畸形和有丝分裂方面的专业知识。 为了实现第二个目标，我们将继续研究一种新的小鼠小头畸形模型， 被称为Mos2。小头症是一种遗传性疾病，大脑体积显着减少 导致智力迟钝。有人提出小头畸形是由神经干缺陷引起的 发育中的新皮层细胞分裂。需要更多的模型来进一步验证这一点 概念.我们对Mos2突变体的初步表征表明，神经干细胞功能受到损害， 在这些小鼠中，由于外显子连接复合物的一个组分发生突变，RNA结合复合物不 与神经发育有关在这个提议中，我们将测试这个复合体是 通过调节不对称细胞分裂来维持神经干细胞。在K99阶段，我们 表征了Mos2突变体中的神经干细胞和分化的神经元群体，以评估 神经干细胞功能被破坏。在ROO阶段，我们将使用细胞生物学和遗传学方法， 询问外显子连接复合体的其他成分是否调节大脑大小和干细胞分裂。这 该提案将为神经发育的调节，小头畸形的机制和其他 神经发育疾病，并特别解决RNA结合蛋白在这些过程中的作用。 追求这些目标将为作为一名独立调查员的职业生涯提供必要的基础， 神经发育

The objectives of this career development proposal are first to expand the Pi's training in neural development and second, to understand why mutation ofan 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. The training for the K99 phase took place at NHGRI on the NIH campus. For the ROO phase of the proposal, the research will be carried out at Duke University Medical Center. 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 continue our study of 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. In the K99 phase, we characterized the neural stem cell and differentiated neuronal populations in Mos2 mutants to evaluate how neural stem cell function is disrupted. In the ROO phase we will use cell biological and genetic approaches to ask if other components of the exon junction complex regulate brain size and stem 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.