Numb and numblike in neural development

神经发育中的麻木和麻木状

• 批准号: 6361576
• 负责人: WEIMIN ZHONG
• 金额: $ 35.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6361576
• 关键词: bromodeoxyuridine; cell cycle; cell differentiation; cell population study; cell proliferation; central neural pathway /tract; developmental neurobiology; gene expression; genetically modified animals; histology; immunologic assay /test; laboratory mouse; lethal genes; membrane proteins; molecular genetics; nerve /myelin protein; nerve stem cell; neurogenesis; neurogenetics; protein isoforms; protein localization; protein structure function; reporter genes; tissue /cell culture; vertebrate embryology

DESCRIPTION (provided by applicant): In Drosophila, asymmetric division by neural precursor cells, a process by which two different daughter cells are generated, plays important roles during nervous system development. The numb gene plays a central role in such asymmetric divisions. numb encodes a membrane-associated protein that becomes asymmetrically localized to only one half of the cell membrane in dividing neural precursor cells necessary for the daughter cells to adopt distinct fates. While mammalian neural progenitor cells are capable of dividing asymmetrically, the precise roles that asymmetric division plays, and what its molecular mechanism is, remain largely unknown. We are studying two mammalian homologues of numb, m-numb and numblike. Based on preliminary studies, we have postulated that, as in Drosophila, asymmetric segregation of m-Numb protein to only one daughter cell provides a cell-intrinsic mechanism that allows neural progenitor cells to divide asymmetrically. Our long term goal is to use m-numb and numblike as an entry point to pinpoint the precise roles that asymmetric cell division plays in mammalian neurogenesis. Towards this end, we have generated conditional m-numb mutant mice as well as numblike mutant mice. We intend to use both in vivo and in vitro approaches to characterize the defects in m-numb and numblike mutant mice by focusing on three types of neural cell fate choices (neuron vs. progenitor, neuron vs. glia, and between different neuronal subtypes). We will further examine whether such defects result from the inability of mutant neural progenitor cells to divide asymmetrically. The application lists four specific aims, the success of which may elucidate the roles that cell-intrinsic mechanisms play in mammalian neural development. Understanding how neural progenitor cells divide asymmetrically may help us to better understand how stem cells are maintained and how diverse neurons are generated during development. Such knowledge can point to mechanisms that cause brain cells to revert to less differentiated states in brain tumors or to degenerate in neurological disorders.

描述（由申请人提供）：在果蝇中，不对称划分 神经前体细胞，两个不同的子细胞是 产生的，在神经系统发育过程中起着重要作用。麻木 基因在这样的不对称分裂中起着核心作用。麻木编码a 膜相关的蛋白质不对称地本地化为一种 一半的细胞膜在划分的神经前体细胞中所必需的 子细胞采取不同的命运。 虽然哺乳动物神经祖细胞能够不对称地分裂，但 不对称分裂起作用的确切作用，其分子是什么 机制是很大程度上未知的。我们正在研究两个哺乳动物的同源物 麻木，妇女和麻木。根据初步研究，我们假设 就像在果蝇中一样 子细胞提供了一种允许神经祖细胞的细胞内部机制 细胞不对称地分裂。 我们的长期目标是使用M-Numb和Numblike作为切入点来查明 不对称细胞分裂在哺乳动物中发挥的确切作用 神经发生。为此，我们已经产生了有条件的m-namb突变体 小鼠以及麻木突变小鼠。我们打算同时使用体内和 体外方法来表征m-nimb和Numblike突变小鼠中的缺陷 通过关注三种类型的神经细胞命运选择（神经元与祖细胞， 神经元与神经胶质，在不同的神经元亚型之间）。我们将进一步 检查这种缺陷是否是由于突变神经无法 祖细胞不对称地分裂。该应用程序列出了四个特定的 目的，成功的成功可以阐明细胞中的角色 机制在哺乳动物神经发育中发挥作用。了解如何神经 祖细胞不对称地分裂可能有助于我们更好地了解 保持干细胞以及在 发展。这样的知识可以指出导致脑细胞的机制 恢复为脑肿瘤中较差的状态或退化 神经系统疾病。