Proj 1: Neurodevelopment Dyx1c1 and Mechanisms of Neuronal Migration in Neocortex

阅读障碍的具体原因尚不清楚。最近的遗传和神经生物学研究加强了 一种有效的假设，即阅读障碍是由早期发育障碍引起的，这些障碍随后会导致 新皮质回路中的功能障碍。在过去的四年里，有4名候选人患有阅读障碍 已经提出了在神经元发育中起作用的易感基因(DYX1C1，KIAA0319， DCDC2和Robo1)。其中三种啮齿动物的同源物Dyxld，KIAA0319和DCDC2已经被 我们的研究小组显示，在新皮质发育中，Robol在神经元迁移中发挥了作用 以前被证明对轴突的生长和引导很重要。该项目的三个目标将进一步 定义Dyxld的细胞和发育作用。拟议的实验将定义组件 Dyxld调控的神经元迁移和分化的研究，并确定 Dyxld和其他对迁徙至关重要的蛋白质。目标将通过在子宫内执行的组合来实现 RNAi、成像、蛋白质-蛋白质相互作用分析和细胞培养方法。新的活体条件 将使用RNAi和过表达方法来探索Dyxld函数的时间依赖性， Dyx1c1功能障碍的潜在发育可逆性。总而言之，这些实验将导致 对基因功能的全面分子和细胞理解，该基因与阅读和 学习障碍。

The specific causes of dyslexia are not yet known. Recent genetic and neurobiological studies strengthen a working hypothesis that dyslexia is caused by early developmental disruptions that subsequently cause functional impairments in neocortical circuits. Within the past four years, 4 candidate dyslexia susceptibility genes with roles in neuronal development have been proposed (DYX1C1, KIAA0319, DCDC2 and ROBO1). Rodent homologs of three of these, Dyxld, Kiaa0319 and Dcdc2 have been shown by our group to play a role in neuronal migration in'developing neocortex, and Robol was previously shown to be important for axon growth and guidance. The three aims of this project will further define the cellular and developmental roles of Dyxld. The proposed experiments will define the components of neuronal migration and differentiation regulated by Dyxld, and identify functional links between Dyxld and other proteins essential to migration. The aims will be executed by a combination of in utero RNAi, imaging, protein-protein interaction assays, and cell culture approaches. Novel in vivo conditional RNAi and overexpression methods will be used to explore the temporal dependence of Dyxld function, and potential developmental reversibility of Dyx1c1 dysfunction. Together, these experiments will lead to a comprehensive molecular and cellular understanding of the function of a gene linked to reading and learning disability.