DEFINING MECHANISMS OF PROGENITOR BALANCE AND NEURONAL CONNECTIVITY

首席调查员(最后、第一、中间)：Anton，Eva S. 项目总结 径向祖细胞作为指导矩阵来协调生成和放置 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 不对称分裂以产生神经源性中间祖细胞(IP)和对称性 IP的增殖有助于迅速扩大皮质神经元的数量。动态感 维持放射状祖细胞和中间祖细胞之间的平衡是根本 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。一旦产生，皮质神经元的生长和连接就能使 大脑皮层基本神经回路的形成。大脑皮层的平衡多样性 前体细胞和由此产生的投射神经元的产生、放置和连接 从而作为指导大脑皮质形成适当连接的蓝图。 发育中的大脑皮层的这些基本特征的破坏是许多 人类神经发育障碍包括小头畸形、巨头畸形、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 指导祖细胞平衡和投射神经元连接仍然是一个谜。这 这项提议旨在弥补我们对大脑皮层形成的理解上的这一空白。在……里面 具体地说，(1)我们将发现径向和中间之间的发展平衡 祖细胞，对于产生正确数量和类型的右侧皮质神经元至关重要 时间，是实现的，(2)定义迄今未知的、初级纤毛介导的引导机制 预测神经元的生长和连接，以及(3)确定这些变化的方式 发育过程可能导致人类潜在的皮质畸形 神经发育障碍。我们的目标是通过创新来实现这些目标 综合应用祖细胞或神经元最新进展的驱动型方法 特定类型的小鼠遗传模型、实时成像、谱系追踪、信号映射 初级纤毛信号的相互作用、光发生和化学发生操纵，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 精神错乱。了解祖细胞和神经元是如何组装、组织和 适当连接以促进大脑皮层的形成，为我们提供了机会 为了更好的诊断和治疗，重新思考和重新绘制皮质生成的规则 对神经发育障碍的洞察。

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.