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 一个工作假设，即诵读困难是由早期发展中断，随后导致 新皮层回路的功能性损伤在过去的四年里，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性基因（DYX 1C 1，KIAA 0319， DCDC 2和ROBO 1）。其中三个的啮齿动物同源物，Dyxld，Kiaa 0319和Dcdc 2已经被发现。 我们的研究小组显示，Robol在“发育中的新皮层”的神经元迁移中发挥作用， 以前被证明对轴突生长和指导很重要。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 神经元迁移和分化的调控Dyxld，并确定之间的功能联系 Dyxld和其他迁移必需的蛋白质。这些目标将通过结合子宫内 RNAi、成像、蛋白质-蛋白质相互作用测定和细胞培养方法。新型体内条件性 RNAi和过表达方法将用于探索Dyxld功能的时间依赖性， 以及Dyx 1c 1功能障碍的潜在发育可逆性。这些实验将导致 对与阅读相关的基因功能的全面的分子和细胞理解， 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.