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Radial Glial Development and Differentiation

放射状胶质细胞的发育和分化

基本信息

批准号：
9116951
负责人：
EVA S ANTON
金额：
$ 38万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116951
关键词：
Affect Brain Brain Diseases Calcium Signaling Cerebral cortex Cerebrum Characteristics Cilia Complex Defect Development Diagnostic Environment Family Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Generations Genes Glial Differentiation Goals Health Human Intellectual functioning disability Joubert syndrome Knowledge Lead Link Maintenance Mechanics Mediator of activation protein Molecular Molecular Models Monomeric GTP-Binding Proteins Mus Mutation Neocortex Neuroglia Neurologic Neurons Outcome Pathway interactions Patients Pharmacogenetics Play Process Radial Receptor Signaling Role SSTR3 gene Signal Transduction Source Staging Stem cells Testing Therapeutic Therapeutic Intervention Variant Work autism spectrum disorder base brain abnormalities brain malformation ciliopathy designer receptors exclusively activated by designer drugs glial cell development migration molecular modeling mutant neurobehavioral disorder novel optogenetics progenitor receptor expression scaffold sensor stem cell niche tool

项目摘要

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.