Stem Cells of the Developing Human Neocortex

描述（由申请人提供）：人类大脑中进化程度最高的结构是新皮层，它负责人类特有的高级认知功能。尽管它很重要，但很少有研究了解人类新皮层是如何发育的，特别是在大多数神经发生的时期，即妊娠的第二个三个月。我们最近在发育中的人类新皮层中描述了一种独特的神经干细胞（oRG细胞），负责大部分皮层神经元的产生。这些细胞位于被称为外室下区（OSVZ）的生发区。值得注意的是，OSVZ在啮齿动物中未被发现，这意味着使用啮齿动物作为模型系统来理解人类新皮层的发育有很大的局限性。本研究的目的是进一步了解OSVZ祖细胞促进人类新皮层发育的机制，主要集中在四个方面：1)oRG细胞的起源及其神经干细胞特性；2)神经发生过程中维持oRG细胞身份和自我更新的细胞和分子机制；3) oRG子细胞通过扩增分裂来增加神经元的产生；4) oRG细胞如何在新皮层中产生和正确分层神经元亚型。通过创新的方法，如细胞标记和克隆分析，细胞行为的实时成像，以及有机型切片培养中的分子遗传技术，提出的研究旨在为理解人类新皮层的发育提供坚实的新基础。这一框架对于正确理解具有遗传或发育起源的人类神经系统疾病至关重要，包括从无脑畸形和小头畸形等皮质畸形到癫痫、自闭症和精神分裂症等更细微的缺陷。了解皮层神经元产生的正确发育序列对神经系统疾病的细胞再生或移植治疗也很重要。

DESCRIPTION (provided by applicant): The most highly evolved structure in the human brain is the neocortex, which is responsible for the higher cognitive functions unique to humans. Despite its importance, little research has been done to understand how the human neocortex develops, especially during the period when most neurogenesis takes place, the second trimester of gestation. We have recently characterized a unique population of neural stem cells (oRG cells) in the developing human neocortex responsible for the majority of cortical neuron production. These cells reside in a germinal region known as the outer subventricular zone (OSVZ). Notably, the OSVZ is not found in the rodent, implying that using the rodent as a model system to understand human neocortical development has significant limitations. The aim of the proposed research is to further understand the mechanisms by which OSVZ progenitor cells contribute to human neocortical development, focusing on four areas: 1) the origin of oRG cells and their neural stem cell properties; 2) the cellular and molecular mechanisms that maintain oRG cell identity and self-renewal during neurogenesis; 3) the amplifying divisions that oRG cell daughters undergo to increase neuronal production; and 4) how oRG cells are required for the production and correct layering of neuronal subtypes in the neocortex. With innovative approaches such as cell labeling and clonal analysis, real-time imaging of cellular behaviors, and molecular genetic techniques in organotypic slice-cultures, the proposed research aims to provide a solid new foundation for understanding human neocortical development. This framework will be essential to correctly understand human neurological diseases that have genetic or developmental origins, ranging from cortical malformations such as lissencephaly and microcephaly to more subtle defects like epilepsy, autism, and schizophrenia. Knowing the proper developmental sequences by which cortical neurons are generated will also be important for cellular regeneration or transplantation therapies for neurological diseases. PUBLIC HEALTH RELEVANCE: The human cerebral cortex is the most highly evolved structure in the human brain and is the site of higher cognitive functions unique to the human species. This study investigates the cellular and molecular mechanisms of human cortex development, focusing on a unique population of neural stem cells not described in rodents. A better understanding of how the human cortex has grown in size and complexity could shed light on a wide assortment of neurodevelopmental disorders, ranging from cortical malformations including microcephaly and lissencephaly to more subtle diseases such as autism and schizophrenia.