DEFINING MECHANISMS OF PROGENITOR BALANCE AND NEURONAL CONNECTIVITY

祖细胞平衡和神经元连接的定义机制

基本信息

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
项目类别：
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

项目摘要

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.

首席研究员（最后、第一、中间）：Anton, Eva S. 项目概要径向祖细胞作为指导矩阵来协调径向祖细胞的生成和放置发育中的大脑皮层中适当数量和类型的神经元。放射状祖细胞不对称分裂产生神经源性中间祖细胞（IP）和对称分裂 IP 的增殖有助于快速扩大皮质神经元数量。动态维持径向祖细胞和中间祖细胞之间的平衡至关重要在正确的时间生成正确数量和类型的投射神经元的重要性在大脑皮层。一旦产生，皮质神经元的生长和连接使大脑皮层基本神经回路的形成。皮质的平衡多样性祖细胞以及由此产生的投射神经元的生成、放置和连接从而作为指导形成适当连接的大脑皮层的蓝图。发育中的大脑皮层的这些基本特征的破坏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，分子逻辑表明指导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理解的这一差距。在特别是，（1）我们将发现桡动脉和中间动脉之间的发育平衡如何祖细胞，对于右侧皮质神经元的正确数量和类型的产生至关重要时间，实现了，（2）定义迄今为止未知的、初级纤毛介导的机制指导预测神经元的生长和连接，以及（3）确定这些变化如何发育过程可能导致人类皮层畸形神经发育障碍。我们的目标是通过创新来实现这些目标驱动方法涉及祖细胞或神经元最新进展的综合应用特定类型小鼠遗传模型、实时成像、谱系追踪、信号传导图谱初级纤毛信号传导的相互作用组、光遗传学和化学遗传学操作、单细胞与神经发育相关的人类突变的基因组学和功能评估失调。了解祖细胞和神经元如何组装、组织和适当连接以促进大脑皮层形成，为我们提供了机会重新思考和重新制定皮质生成规则，以更好地诊断和治疗对神经发育障碍的见解。