Radial Glial Development and Differentiation

 描述（由申请人提供）：初级纤毛活性对于大脑皮层中放射状祖细胞的形成至关重要。放射状祖细胞作为神经元的来源，并作为神经元迁移和放置的指导性支架。它们协调发育中的大脑皮层中适当数量和类型的神经元的产生和放置。人类纤毛功能的破坏会导致严重的大脑异常和智力残疾。然而，很少有人知道的纤毛信号机制的皮质祖细胞的发展和由此产生的大脑皮质的形成。在这里，我们建议测试的假设，即主要纤毛信号的基础上的干细胞样和迁移支架功能的放射状祖细胞在大脑皮层系统描绘的机制基础和影响纤毛衍生的信号在放射状祖细胞的形成，组织和功能。我们的实验室先前表明，RG的形成和功能依赖于Arl13b，这是一种已知为纤毛信号传导所必需的小GT。我们将（a）确定Arl 13 B调节桡骨祖细胞功能的纤毛机制，（B）描述人ARL 13 B的突变是否有助于在纤毛病中祖细胞驱动的脑异常，和（c）化学遗传学地询问Arl 13 B相关的纤毛GPCR信号传导在桡骨祖细胞功能中的总体意义。总的来说，这项工作的结果将揭示初级纤毛信号传导的综合作用，必要的辐射状祖细胞的适当发展。重要的是，纤毛相关的分子信号级联反应和神经发育通路的整体相关的大脑皮层的形成，将使我们能够制定最佳的诊断和治疗策略，神经发育性脑疾病引起的纤毛功能障碍。

 DESCRIPTION (provided by applicant): Primary cilia activity is essential for the formation of radial progenitors in cerebral cortex. Radial progenitors function as a source of neurons and as an instructive scaffold for neuronal migration and placement. They coordinate the generation and placement of appropriate number and types of neurons in the developing cerebral cortex. Disrupted cilia function in humans results in profound brain abnormalities and intellectual disabilities. However, little is known about the ciliary signaling mechanisms underlying the cortical progenitor development and the resultant cerebral cortical formation. Here, we propose to test the hypothesis that primary cilia signaling underlies the stem cell-like and migratory scaffold functions of the radial progenitors in cerebral cortex by systematically delineating the mechanistic underpinnings and impact of cilia derived signaling in radial progenitor formation, organization, and function. Our lab previously showed that RG formation and function is dependent on Arl13b, a small GTPase known to be necessary for cilia signaling. We will (a) determine the ciliary mechanisms through which Arl13b regulates radial progenitor functions, (b) delineate if mutations of human ARL13B contribute to progenitor driven brain anomalies in ciliopathies, and (c) chemogenetically interrogate the overall significance of Arl13b associated ciliary GPCR signaling in the functions of radial progenitors. Collectively, the outcome of this work will reveal the integrative role of primary cilia signaling necessary for the appropriate development of radial progenitors. Importantly, delineation of the cilia-related molecular signaling cascades and neurodevelopmental pathways integrally related to the formation of cerebral cortex will enable us to devise optimal diagnostic and therapeutic strategies for neurodevelopmental brain disorders resulting from cilia dysfunction.