DYSLEXIA SUSCEPTIBILITY GENES AND MECHANISMS OF NEURONAL DEVELOPMENT

描述(申请人提供)：阅读障碍(RD)或阅读障碍是儿童最常见的学习障碍。虽然阅读障碍的具体原因尚不清楚，但最近的遗传学和神经生物学研究加强了一个有效的假说，即阅读障碍是由早期发育中断引起的，随后导致新皮质回路的功能障碍。在过去的三年里，已经提出了四个候选阅读障碍易感基因(DYX1C1、KIAA0319、DCDC2和Robo1)，这四个基因都在神经元发育中发挥作用。其中三个啮齿动物的同源物Dyx1c1，KIAA0319和DCDC2已被证明在新皮质发育的神经元迁移中发挥作用，而Robo1先前被证明对轴突的生长和引导具有重要作用。该项目的前三个目标将进一步定义KIAA0319和DCDC2的细胞和发育作用，这两个基因目前作为阅读障碍易感基因具有最强的遗传支持。这三个目的是确定DCDC2和KIAA0319调控神经元迁移的成分，确定KIAA0319和DCDC2在神经元迁移中的功能联系，并确定DCDC2和KIAA0319的功能必需的蛋白质结构域。这些目标将通过结合宫内RNAi、成像和细胞培养方法来实现。为了研究KIAA0319和DCDC2之间的相互作用，提出了一种新的RNAi和电穿孔的组合方法。最后，与目前致力于在人类群体中识别更多阅读障碍易感基因的小组合作，我们建议测试新的候选阅读障碍易感基因在神经元迁移和发育中的发育作用。综上所述，这些实验的结果将揭示候选阅读障碍易感基因在神经元发育中的细胞功能，这应该有助于最终理解这种学习障碍的根本原因。 项目简介：阅读障碍(RD)或阅读障碍是儿童最常见的学习障碍。虽然阅读障碍的具体原因尚不清楚，但最近的遗传学和神经生物学研究加强了一个有效的假说，即阅读障碍是由早期发育中断引起的，随后导致新皮质回路的功能障碍。这些拟议的实验结果将揭示候选阅读障碍易感基因在神经元发育中的细胞功能，这将有助于最终理解这种学习障碍的潜在原因。

DESCRIPTION (provided by applicant): Reading disability (RD) or dyslexia is the most common learning disorder in children. While 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 three years four candidate dyslexia susceptibility genes have been proposed (DYX1C1, KIAA0319, DCDC2 and ROBO1), and all four play roles in neuronal development. Rodent homologs of three of these, Dyx1c1, Kiaa0319 and Dcdc2 have been shown to play a role in neuronal migration in developing neocortex, and Robo1 was previously shown to be important for axon growth and guidance. The first three aims of the project will further define the cellular and developmental roles of Kiaa0319 and Dcdc2, the two genes currently with strongest genetic support as dyslexia susceptibility genes. These three aims are to determine the components of neuronal migration regulated by dcdc2 and kiaa0319, to determine functional links between kiaa0319 and dcdc2 in neuronal migration, and to determine the functionally necessary protein domains of dcdc2 and kiaa0319. The aims will be carried out by a combination of in utero RNAi, imaging, and cell culture approaches. Novel combinatorial methods of RNAi and electroporation are proposed to investigate interaction between Kiaa0319 and Dcdc2. Finally, in collaboration with groups currently working on identifying additional dyslexia susceptibility genes in human populations, we propose to test the developmental roles of new candidate dyslexia susceptibility genes in neuronal migration and development. Together, results form these experiments will reveal the cellular functions of candidate dyslexia susceptibility genes in neuronal development, and this should contribute to an eventual understanding of the underlying causes of this learning disorder. Project Narrative: Reading disability (RD) or dyslexia is the most common learning disorder in children. While 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. Results form these proposed experiments will reveal the cellular functions of candidate dyslexia susceptibility genes in neuronal development, and this should contribute to an eventual understanding of the underlying causes of this learning disorder.