Development and Expansion of the Human Cerebral Cortex

该计划的一个主要长期目标是了解人类大脑发育和神经发育疾病的起源。大脑皮层是一种结构，其中模型系统，如小鼠或大鼠，可能无法捕获与理解人类发育和疾病相关的结构和功能的复杂性。该提案旨在通过使用“脑类器官”研究由人干细胞衍生的体外模型系统补充的原代组织来解决我们对人类皮质发育的理解中的差距。了解人类大脑发育的特定方面不仅对了解神经发育障碍的病因至关重要，包括自闭症和精神分裂症，并最终开发治疗方法，而且还将有助于我们了解人类皮层的进化，神经细胞类型的多样性和谱系，以及皮层扩展的机制-它将有助于定义是什么使我们与众不同。发育中的人脑包含一个扩大的增殖区，即外室下区（OSVZ），这在啮齿动物中不存在。这项研究将针对OSVZ中发现的两种最近发现的神经祖细胞类型，即外放射状胶质细胞（oRG）和中间祖细胞（IP）。这些细胞类型特别重要，因为它们是人类大脑巨大发育和进化扩张的基础。该提案旨在阐明人类皮质发育的复杂性，其组成oRG和IP神经祖细胞及其后代的基因组，细胞和行为特征，通过神经发生的关键阶段。我们计划发现谱系轨迹，定义祖先后代的关系，并确定克隆后代的细胞命运。我们将使用新的oRG和IPC标记物来丰富祖细胞群进行分析，探索调节IP细胞扩增的细胞内信号传导网络，研究不同神经源性小生境在创造神经元多样性中的作用，并研究可能调节IPC神经发生的神经元至祖细胞信号传导通路。此外，我们将探讨oRG和IPC在无脑畸形和相关神经发育疾病中的作用，并寻求oRG细胞和侵袭性胶质母细胞瘤之间有趣的关系。这些雄心勃勃的目标是可以实现的，由于最近的技术进步，包括单细胞基因组学，生物信息学，真实的时间成像的主要组织样本，和体外模型的人皮质发育。这一结果有望改变我们对健康和疾病中人类大脑发育的理解。

A major long-term goal of this proposal is to understand human brain development and the origins of neurodevelopmental diseases. The cerebral cortex is a structure where model systems, such as mouse or rat, may not capture the complexity of architecture and function relevant for understanding human development and disease. This proposal aims to address the gap in our understanding of human cortical development through the study of primary tissue complemented by human stem cell-derived in vitro model systems, using “cerebral organoids”. Understanding human-specific aspects of brain development is not only critically important for understanding the etiology of neurodevelopmental disorders, including autism and schizophrenia and ultimately developing therapies, but will also benefit our understanding of human cortical evolution, the diversity and lineage of neural cell types, and the mechanisms of cortical expansion - it will help define what makes us unique. The developing human brain contains an enlarged proliferative region, the outer subventricular zone (OSVZ) that is not present in rodents. This study will target two recently discovered neural progenitor cell types found in the OSVZ, outer radial glia (oRG) and intermediate progenitor (IP) cells. These cell types are particularly important as they underlie the huge developmental and evolutionary expansion of the human brain. This proposal seeks to illuminate the complexity of human cortical development in terms of the genomic, cellular, and behavioral features of its constituent oRG and IP neural progenitor cells and their progeny through the key stages of neurogenesis. We plan to discover lineage trajectories that define progenitor-progeny relationships and determine the cellular fates of clonal descendants. We will use novel oRG and IPC markers to enrich progenitor cell populations for analysis, explore the intracellular signaling networks that regulate IP cell expansion, investigate the role of distinct neurogenic niches in creating neuronal diversity, and examine neuron to progenitor signaling pathways that may regulate IPC neurogenesis. Additionally, we will explore the role of oRGs and IPCs in lissencephaly and related neurodevelopmental diseases, and pursue an intriguing relationship between oRG cells and invasive glioblastoma. These ambitious goals are attainable due to recent technological advances, including improvements in single cell genomics, bioinformatics, real time imaging of primary tissue samples, and in vitro models of human cortical development. The outcome holds promise to transform our understanding of human brain development in health and disease.