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：
7144736
负责人：
WEIMIN ZHONG
金额：
$ 46.64万
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 2011-07-31
项目状态：
已结题

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）：我们研究控制哺乳动物神经茎（祖细胞）细胞行为的分子和细胞机制，特别是它们如何通过使用小鼠中的胚胎中枢神经系统作为模型系统来平衡自我更新和分化的竞争需求。我们对不对称细胞分裂特别感兴趣，该过程通过该细胞分裂以产生两个不同的子细胞。这种分裂在产生无脊椎动物的细胞多样性方面起着关键作用。我们已经假设，哺乳动物神经祖细胞通过不对称地分裂以产生子祖细胞和神经元来平衡自我更新和分化，并且在这样的分区中，哺乳动物成像蛋白，m- numb and numblike（Numblike（Numbl）），不对称地向祖先子分散，以促进其效率。通过过去四年由美国国立卫生研究院资助的研究，我们证明了M-NEMB和NUMBL是多余的，但对于维持神经祖细胞细胞是必不可少的，并且不对称的麻醉隔离是至关重要的，因此，不对称细胞的分裂确实至关重要，对于在小鼠胚胎发生过程中，神经发生对于正常进行神经发生而言至关重要。作为这些发现的自然扩展，这种更新应用旨在阐明使蛋白质在哺乳动物神经发生过程中指定细胞命运的分子途径。具体而言，我们将使用小鼠和果蝇进行一系列功能丧失研究，以检查一种新的机制，通过该机制，高尔基体在祖细胞周期中通过释放出臭名昭著的蛋白质，Merry Magpie（MRGI）来使Numb sigitate在两种味道中的动作siply twockiss siquess siqusion sikish twockish n two n siitosis，从而在祖细胞周期中协调细胞触发时间的定时。该应用的目的是（1）测试MRGI和NUMB蛋白是细胞剂量规范中必不可少的伙伴的假设，（2）检查MRGI在Numb信号中从高尔基人发出的MRGI释放的重要性（3）确定在小鼠神经发生过程中MRGI发挥的精确作用，以分配MRGGI函数，并分配MRGGI Domains。如果成功的话，拟议的研究可能揭示了有关发育神经生物学和神经干细胞生物学的一些最基本的机制。这种知识可能指出的机制会导致脑细胞恢复为脑肿瘤中分化较少的状态或神经系统疾病中的变质。