Analysis of the Exon Junction Complex in Neural Development and Microcephaly

这项职业发展建议的目标是首先扩大PI在神经方面的培训 第二，了解为什么RNA结合复杂成分的突变会导致 缩小了大脑的尺寸。对于第一个目标，我们制定了职业发展计划，以提供 为私家侦探作为独立调查员取得成功所需的科学和职业培训。这个 K99阶段的培训在NIH校园内的NHGRI进行。对于建议书的Roo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 它们汇集了小鼠胚胎学、神经发育、小头畸形和有丝分裂方面的专业知识。 为了第二个目标，我们将继续研究我们现有的一种新的小头畸形小鼠模型。 已识别的名为MoS2。小头畸形症是一种遗传性疾病，其大脑大小显著缩小。 导致精神发育迟滞。小头畸形被认为是由神经干细胞的缺陷引起的。 发育中的新皮质中的细胞分裂。需要更多的模型来进一步验证这一点 概念。我们对MoS2突变体的初步描述表明，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体的一个组成部分发生突变，RNA结合复合体不会 之前被认为与神经发育有关。在这个提议中，我们将检验这样的假设：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所需的。在K99阶段，我们 鉴定MoS2突变体中的神经干细胞和分化的神经元群体，以评估如何 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来 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、小头畸形的机制等提供洞察力 神经发育疾病，并特别涉及RNA结合蛋白在这些过程中的作用。 追求这些目标将为成为一名独立调查员提供必要的基础 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.