Functional Analysis of Mouse Numb and Numblike in Neural Development

小鼠麻木和麻木样神经发育的功能分析

基本信息

批准号：
7899881
负责人：
WEIMIN ZHONG
金额：
$ 47.66万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7899881
关键词：
Adopted Affect Alleles Behavior Binding Binding Proteins Biological Assay Biological Models Biology Brain Neoplasms Cell Cycle Cell division Cell membrane Cells Cytosol Daughter Development Drosophila genus Embryo Embryonic Development Equilibrium Funding Genes Genetic Golgi Apparatus Homologous Gene Interphase Invertebrates Knowledge Manuscripts Mitosis Modeling Molecular Mus Mutant Strains Mice Nervous system structure Neuraxis Neurons Pathway interactions Play Population Preparation Process Proteins Research Role Series Signal Transduction Signaling Protein Specific qualifier value Stem cells System Testing Time To specify United States National Institutes of Health brain cell cell fate specification daughter cell developmental neurobiology embryonic stem cell gain of function homologous recombination interest loss of function mouse Numb protein mutant nerve stem cell nervous system disorder neurodevelopment neurogenesis novel numb protein precursor cell progenitor relating to nervous system research study segregation self-renewal stem

项目摘要

DESCRIPTION (provided by applicant): We study the molecular and cellular mechanisms that govern the behavior of mammalian neural stem (progenitor) cells, in particular how they balance the competing needs of self-renewal and differentiation, by using the embryonic central nervous system in mice as a model system. We are particularly interested in asymmetric cell division, a process by which a cell divides to produce two different daughter cells. Such divisions play a critical role in generating cellular diversity in invertebrates. We have postulated that mammalian neural progenitor cells balance self-renewal and differentiation by dividing asymmetrically to produce a daughter progenitor cell and a neuron and that in such divisions, mammalian Numb proteins, m- Numb and Numblike (Numbl), asymmetrically segregate to the progenitor daughter to promote its fate. Through research funded by the National Institutes of Health in the last four years, we demonstrated that m-Numb and Numbl are redundant but essential for maintaining neural progenitor cells and that asymmetric Numb segregation and, therefore, asymmetric cell division are indeed critical for neurogenesis to proceed normally during mouse embryogenesis. As a natural extension of these findings, this renewal application seeks to elucidate the molecular pathway that enables Numb proteins to specify cell fates during mammalian neurogenesis. Specifically, we will perform a series of gain- and loss-of-function studies using mice and Drosophila to examine a novel mechanism by which the Golgi apparatus coordinates the timing of cell-fate determination during the progenitor cell cycle by releasing a Numb-binding protein, MERRY MAGPIE (MRGI), to activate Numb signaling only during mitosis to distinguish the two daughter cells. The aims of this application are (1) to test the hypothesis that MRGI and Numb proteins are essential partners in cell-fate specification, (2) to examine the importance of MRGI release from the Golgi in Numb signaling, (3) to determine the precise roles that MRGI plays during mouse neurogenesis, and (4) to assign function to different MRGI domains. If successful, the proposed research may reveal some of the most fundamental mechanisms governing developmental neurobiology and the biology of neural stem cells. Such knowledge may point to mechanisms that cause brain cells to revert to less differentiated states in brain tumors or degenerate in neurological disorders.

描述（由申请人提供）：我们通过利用胚胎中枢神经系统，研究控制哺乳动物神经干（祖）细胞行为的分子和细胞机制，特别是它们如何平衡自我更新和分化的竞争需求。小鼠作为模型系统。我们对不对称细胞分裂特别感兴趣，这是细胞分裂产生两个不同子细胞的过程。这种分裂在无脊椎动物细胞多样性的产生中起着至关重要的作用。我们假设哺乳动物神经祖细胞通过不对称分裂产生子代祖细胞和神经元来平衡自我更新和分化，并且在这种分裂中，哺乳动物 Numb 蛋白、m-Numb 和 Numblike (Numbl) 不对称地分离到祖细胞女儿促其缘。通过过去四年美国国立卫生研究院资助的研究，我们证明 m-Numb 和 Numbl 是多余的，但对于维持神经祖细胞至关重要，并且不对称的 Numb 分离以及因此不对称的细胞分裂对于神经发生确实至关重要。在小鼠胚胎发生过程中正常进行。作为这些发现的自然延伸，这一更新应用旨在阐明使 Numb 蛋白在哺乳动物神经发生过程中指定细胞命运的分子途径。具体来说，我们将使用小鼠和果蝇进行一系列功能获得和丧失的研究，以检查一种新机制，通过该机制，高尔基体通过释放麻木结合来协调祖细胞周期中细胞命运决定的时间。 MERRY MAGPIE (MRGI) 蛋白仅在有丝分裂期间激活 Numb 信号以区分两个子细胞。本应用的目的是 (1) 检验 MRGI 和 Numb 蛋白是细胞命运规范中重要伙伴的假设，(2) 检查高尔基体释放 MRGI 在 Numb 信号传导中的重要性，(3) 确定MRGI 在小鼠神经发生过程中发挥的精确作用，以及 (4) 将功能分配给不同的 MRGI 域。如果成功，拟议的研究可能会揭示一些控制发育神经生物学和神经干细胞生物学的最基本机制。这些知识可能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神经系统疾病中退化的机制。