Stem Cells of the Developing Human Neocortex

描述(申请人提供)：人脑中进化程度最高的结构是新皮质，负责人类特有的高级认知功能。尽管它很重要，但很少有人研究人类新皮质是如何发育的，特别是在大多数神经发生的时期，也就是怀孕的第二个三个月。我们最近在发育中的人类新皮质中描述了一组独特的神经干细胞(org细胞)，负责大部分皮质神经元的产生。这些细胞位于一个称为外室下区(OSVZ)的生发区。值得注意的是，在啮齿动物中没有发现OSVZ，这意味着使用啮齿动物作为模型系统来理解人类新皮质的发育有很大的局限性。这项研究的目的是为了进一步了解OSVZ前体细胞对人类新皮质发育的作用机制，主要集中在四个方面：1)组织细胞的起源及其神经干细胞的特性；2)在神经发生过程中维持组织细胞特性和自我更新的细胞和分子机制；3)组织细胞子体经历的放大分裂以增加神经元的产生；以及4)组织细胞如何在新皮质中产生和正确分层神经元亚型。通过细胞标记和克隆分析、细胞行为的实时成像以及器官型切片培养中的分子遗传学技术等创新方法，本研究旨在为理解人类新皮质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疾病至关重要，这些疾病包括无脑和小头畸形等皮质畸形，以及癫痫、自闭症和精神分裂症等更微妙的缺陷。了解皮质神经元生成的正确发育顺序对细胞再生或神经疾病的移植治疗也很重要。

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.