Development and Expansion of the Human Cerebral Cortex

这项提议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。本提案旨在通过使用“脑类器官”，通过研究原代组织补充人类干细胞衍生的体外模型系统，解决我们对人类皮层发育的理解差距。了解大脑发育的人类特异性方面不仅对理解神经发育障碍（包括自闭症和精神分裂症）的病因以及最终开发治疗方法至关重要，而且还有助于我们理解人类皮层进化、神经细胞类型的多样性和谱系以及皮层扩张的机制——它将有助于定义使我们与众不同的东西。发育中的人脑包含一个扩大的增殖区域，即外室下区（OSVZ），这在啮齿动物中是不存在的。本研究将针对最近在OSVZ中发现的两种神经祖细胞类型，外放射状胶质细胞（oRG）和中间祖细胞（IP）。这些细胞类型尤其重要，因为它们是人类大脑巨大发育和进化扩张的基础。本研究旨在通过神经发生的关键阶段阐明人类皮层发育的复杂性，包括其组成的oRG和IP神经祖细胞及其后代的基因组、细胞和行为特征。我们计划发现谱系轨迹，定义祖-子关系，并确定克隆后代的细胞命运。我们将使用新的oRG和IPC标记来丰富用于分析的祖细胞群，探索调节IP细胞扩增的细胞内信号网络，研究不同神经源性生态位在创造神经元多样性中的作用，并检查可能调节IPC神经发生的神经元到祖细胞的信号通路。此外，我们将探索oRG细胞和IPCs在无脑畸形和相关神经发育疾病中的作用，并寻求oRG细胞与侵袭性胶质母细胞瘤之间的有趣关系。由于最近的技术进步，包括单细胞基因组学、生物信息学、原代组织样本实时成像和人类皮质发育体外模型的改进，这些雄心勃勃的目标是可以实现的。这一结果有望改变我们对人类大脑在健康和疾病方面发育的理解。

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.