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，不对称分裂 神经前体细胞，两个不同子细胞的过程 生成，在神经系统发育过程中发挥重要作用。麻木的 基因在这种不对称分裂中起着核心作用。麻木编码a 膜相关蛋白不对称地定位于仅一个 神经前体细胞分裂所必需的细胞膜的一半 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分裂， 不对称分裂所起的确切作用及其分子结构 其机制仍很大程度上未知。我们正在研究两种哺乳动物的同源物 麻木、m-麻木和麻木状。根据初步研究，我们假设 与果蝇一样，m-Numb 蛋白不对称分离为仅一种 子细胞提供了一种细胞内在机制，允许神经祖细胞 细胞不对称分裂。 我们的长期目标是使用 m-numb 和 numblike 作为精确定位的切入点 不对称细胞分裂在哺乳动物中发挥的精确作用 神经发生。为此，我们生成了条件 m-numb 突变体 小鼠以及麻木的突变小鼠。我们打算在体内和体内使用 表征 m 麻木和麻木样突变小鼠缺陷的体外方法 通过关注三种类型的神经细胞命运选择（神经元与祖细胞， 神经元与神经胶质细胞，以及不同神经元亚型之间）。我们将进一步 检查这些缺陷是否是由于突变神经元的无能力造成的 祖细胞不对称分裂。该申请列出了四项具体内容 目标，其成功可能会阐明细胞内在的作用 机制在哺乳动物神经发育中发挥作用。了解神经元如何 祖细胞不对称分裂可能有助于我们更好地理解如何分裂 干细胞的维持以及如何在过程中产生不同的神经元 发展。这些知识可以指出导致脑细胞 在脑肿瘤中恢复到分化程度较低的状态或在脑肿瘤中退化 神经系统疾病。