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.
Little is known about the cellular and molecular signaling that guide progenitor development and the resultant cerebral cortical. However, the spectrum of neurological defects associated with primary cilia dysfunction in humans, suggest that primary cilia in progenitors may play critical and specific roles in the formation and function of cortical progenitors in the developing cerebral cortex. Therefore, defining how primary cilia signaling regulates progenitor development in cerebral cortex will be essential to understand the fundamental mechanisms of cerebral cortical formation. This knowledge could help identify and rationalize novel targets for therapeutic interventions for cilia dysfunction-related brain disordes.
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