Radial Glial Development and Differentiation

 描述(申请人提供)：初级纤毛活动对大脑皮层放射状祖细胞的形成是必不可少的。放射状祖细胞既可以作为神经元的来源，也可以作为神经元迁移和放置的指导支架。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。人类纤毛功能紊乱会导致严重的大脑异常和智力残疾。然而，对皮层前体发育和由此产生的大脑皮质形成背后的纤毛信号机制知之甚少。在这里，我们建议通过系统地描述纤毛衍生信号在放射状前体细胞的形成、组织和功能中的机制基础和影响来检验这一假说，即初级纤毛信号是大脑皮质中放射状前体的干细胞样和迁移支架功能的基础。我们的实验室以前表明，RG的形成和功能依赖于Arl13b，Arl13b是一种已知的纤毛信号所必需的小GTP酶。我们将(A)确定Arl13b调节放射状祖细胞功能的纤毛机制，(B)描述人类Arl13b突变是否导致纤毛疾病中祖先驱动的脑异常，以及(C)从化学遗传学角度询问Arl13b相关的纤毛GPCR信号在放射状祖细胞功能中的整体意义。总而言之，这项工作的结果将揭示初级纤毛信号对放射状祖细胞的适当发育所必需的整合作用。重要的是，描绘纤毛相关的分子信号级联和与大脑皮层形成完整相关的神经发育通路将使我们能够为纤毛功能障碍引起的神经发育脑疾病设计出最佳的诊断和治疗策略。

 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.