DEFINING MECHANISMS OF PROGENITOR BALANCE AND NEURONAL CONNECTIVITY

祖细胞平衡和神经元连接的定义机制

• 批准号: 10614533
• 负责人: EVA S ANTON
• 金额: $ 54.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614533
• 关键词: Cells; Cerebral cortex; Cilia; Cortical Malformation; Development; Developmental Process; Diagnostic; Epilepsy; Equilibrium; Evaluation; Foundations; Generations; Genetic Models; Genomics; Goals; Growth; Human; Image; Logic; Macrocephaly; Maintenance; Maps; Mediating; Microcephaly; Modeling; Molecular; Mutation; Neurodevelopmental Disorder; Neurons; Population; Principal Investigator; Production; Proliferating; Radial; Schizophrenia; Services; Signal Transduction; Therapeutic; Time; Work; autism spectrum disorder; brain malformation; genetic manipulation; innovation; insight; lissencephaly; mouse genetics; neuronal circuitry; neuronal growth; optogenetics; progenitor

Principal Investigator (Last, First, Middle): Anton, Eva S. PROJECT SUMMARY Radial progenitors serve as an instructive matrix to coordinate the generation and placement of appropriate number and types of neurons in the developing cerebral cortex. Radial progenitors divide asymmetrically to generate neurogenic intermediate progenitors (IPs) and the symmetric proliferation of IPs serves to rapidly expand cortical neuronal population. The dynamic maintenance of the balance between radial and intermediate progenitors is of fundamental importance to the generation of right number and types of projection neurons at the right time in the cerebral cortex. Once generated, growth and connectivity of cortical neurons enables the formation of basic neuronal circuitry in the cerebral cortex. The balanced diversity of cortical progenitors and the resultant generation, placement, and connectivity of projection neurons thus serve as a blueprint to guide the formation of an appropriately wired cerebral cortex. Disruptions in these essential features of the developing cerebral cortex are at the core of many human neurodevelopmental disorders including microcephaly, macrocephaly, lissencephaly, epilepsy, schizophrenia, and autism spectrum disorders. However, the molecular logic that instructs progenitor balance and projection neuronal connectivity remains an enigma. This proposal aims to remedy this gap in our understanding of cerebral cortical formation. In particular, (1) we will discover how the developmental balance between radial and intermediate progenitors, vital for the production of right number and types of cortical neurons at the right time, is achieved, (2) define hitherto uncharted, primary cilia-mediated mechanisms guiding projection neuronal growth and connectivity, and (3) determine how changes in these developmental processes can cause cortical malformations underlying human neurodevelopmental disorders. We aim to make these goals attainable by using an innovation driven approach that involves combined application of latest advances in progenitor or neuron type specific mouse genetic models, live imaging, lineage tracing, mapping of signaling interactomes, optogenetic and chemogenetic manipulation of primary cilia signaling, single cell genomics, and functional evaluation of human mutations associated with neurodevelopmental disorders. Understanding how progenitors and neurons are assembled, organized, and connected appropriately to facilitate cerebral cortical formation, offers us the opportunity to rethink and redraw the rules of corticogenesis in the service of better diagnostic and therapeutic insights into neurodevelopmental disorders.

主要研究者（最后、第一、中间）：Anton、伊娃S。 项目摘要 径向祖细胞充当指导性矩阵以协调 发育中的大脑皮层神经元的数量和类型。辐射状祖细胞 不对称分裂产生神经源性中间祖细胞（IP）， IP的增殖用于快速扩增皮质神经元群体。动态 维持径向祖细胞和中间祖细胞之间的平衡是至关重要的 在正确的时间产生正确数量和类型的投射神经元的重要性 在大脑皮层中。一旦产生，皮层神经元的生长和连接使神经元的生长和连接成为可能。 大脑皮层中基本神经元回路的形成。大脑皮层的平衡多样性 祖细胞以及投射神经元的产生、放置和连接 从而作为一个蓝图，指导形成一个适当的有线大脑皮层。 发育中的大脑皮层的这些基本特征的中断是许多疾病的核心。 人类神经发育障碍，包括小头畸形，大头畸形，无脑畸形， 癫痫、精神分裂症和自闭症谱系障碍。然而，分子逻辑 指示祖细胞平衡和投射神经元连接仍然是一个谜。这 该提案旨在弥补我们对大脑皮层形成的理解中的这一空白。在 特别是，（1）我们将发现径向和中间之间的发展平衡， 前体细胞，对于在右侧产生正确数量和类型的皮质神经元至关重要。 时间，实现，（2）定义迄今未知的，主要纤毛介导的机制，指导 预测神经元的生长和连接，以及（3）确定这些变化 发育过程会导致大脑皮层畸形， 神经发育障碍我们的目标是通过使用创新来实现这些目标。 驱动的方法，涉及祖细胞或神经元的最新进展的组合应用 型特异性小鼠遗传模型，活体成像，谱系追踪，信号定位 相互作用基因组，初级纤毛信号传导的光遗传学和化学遗传学操纵，单细胞 基因组学和与神经发育相关的人类突变的功能评价 紊乱了解祖细胞和神经元是如何组装，组织和 适当地连接，以促进大脑皮层的形成，为我们提供了机会， 重新思考和重新绘制皮质生成的规则，以更好地诊断和治疗 对神经发育障碍的深入了解