DROSOPHILA NEURONAL TEMPORAL IDENTITY

果蝇神经元时间特性

• 批准号: 7884505
• 负责人: TZUMIN LEE
• 金额: $ 37.01万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884505
• 关键词: 5' Untranslated Regions; Address; Adult; Back; Behavior; Biological Models; Birth Order; Brain; Brain Stem; Cells; Characteristics; Cis-Acting Sequence; Clinical; Color; Complex; Degenerative Disorder; Development; Developmental Process; Drosophila genus; Employee Strikes; Exhibits; Future; Gelshift Analysis; Gene Silencing; Generations; Genes; Genetic; Genetic Screening; Goals; Injury; Intervention; Knowledge; Lateral; Lobe; Mediating; Messenger RNA; Mitotic; Molecular; Morphogenesis; Morphology; Mushroom Bodies; Neurons; Neurosciences; Nuclear Protein; Nuclear Proteins; Organism; Pathway interactions; Pattern; Population; Process; Property; Proteins; RNA Interference; Regulatory Element; Research; Role; Specific qualifier value; Staging; Stem cells; System; Testing; Time; Trans-Activators; Translations; Untranslated Regions; Zinc Fingers; cell fate specification; crosslink; design; developmental disease; insight; loss of function; neuroblast; neurogenesis; novel; public health relevance; relating to nervous system; research study; tool; trait

DESCRIPTION (provided by applicant): To unravel how the astonishing diversity of neurons is derived through birth order/timing-dependent cell fate specification, we propose to use sophisticated genetic tools in a relatively simple organism, the fruit fly Drosophila, to study the mechanisms of neuronal temporal identity. From a genetic mosaic screen, we have identified the Drosophila Chinmo BTB-zinc finger protein, and in particular its gradients through neurogenesis, as a novel mechanism conferring neuronal temporal identity. We have further demonstrated that the establishment of the Chinmo gradient involves the differential translation of chinmo messages carrying a 1.7kb-long 5'UTR. In this proposal, we will (1) examine the generality of Chinmo function in specifying neuronal temporal identity, (2) investigate the chinmo 5'UTR-dependent translational control for tracing back the origin for Chinmo-governed neuronal temporal cell fate specifications, and (3) screen for additional genes that may act within the Chinmo pathway or operate independently to control neuronal temporal identity. This study, including thorough analysis of Chinmo function and systematical identification of temporal identity genes, promises to provide major insights into the mechanisms governing birth order/timing-dependent neuronal diversification, a crucial developmental process in the brain. PUBLIC HEALTH RELEVANCE: The brain is composed of a monumental number of different types of neurons. These neurons interact with each other forming the complex brain circuits that underlie behavior and the coordination of the vital functions of the body. Congenital and developmental disorders that interfere with the formation of neuronal diversity have drastic consequences for brain function. Further, knowledge about the stem cells that in the brain give rise to this diversity may provide powerful clinical approaches for interventions during degenerative disorders or after injury. The goal of this project is to understand how brain stem cells give rise to neuronal diversity according to the order in which neurons are born (temporal identity). To address this question we are using a powerful model system, the fruit fly Drosophila, in which the genes controlling temporal identity can be isolated in an efficient manner. Our studies in this system have isolated a gene, called chinmo (chronologically inappropriate morphogenesis) with central roles in this process. In this project we will elucidate the mechanisms of Chinmo function by (a) determining if it is a universal temporal identity gene, or whether there are other genes that also can fulfill this function, (b) determining the mechanisms by which Chinmo functions, and (c) searching for other cell identity genes that may function with Chinmo, or in a Chinmo-independent fashion to confer temporal identity. We expect that the studies proposed will have a fundamental impact in our understanding of how neuronal diversity is generated, how this neuronal diversity is encoded in stem cells, and how these stem cells can be manipulated in order to generate particular neuron populations.

描述（由申请人提供）：为了揭示神经元的惊人多样性是如何通过出生顺序/时间依赖性细胞命运规范获得的，我们建议在相对简单的生物体中使用复杂的遗传工具，果蝇果蝇，研究神经元时间身份的机制。从遗传镶嵌屏幕，我们已经确定了果蝇Chinmo BTB-锌指蛋白，特别是其梯度通过神经发生，作为一种新的机制，赋予神经元的时间身份。我们进一步证明了Chinmo梯度的建立涉及携带1.7kb长的5 'UTR的Chinmo信息的差异翻译。在这个提议中，我们将（1）检查Chinmo功能在指定神经元时间身份中的一般性，（2）研究Chinmo 5 'UTR依赖的翻译控制，以追溯Chinmo支配的神经元时间细胞命运规范的起源，以及（3）筛选可能在Chinmo通路内起作用或独立操作以控制神经元时间身份的其他基因。这项研究，包括Chinmo功能的深入分析和时间身份基因的系统识别，有望提供重要的见解出生顺序/时间依赖的神经元多样化，在大脑中的一个重要的发育过程的机制。 公共卫生相关性：大脑由大量不同类型的神经元组成。这些神经元相互作用，形成复杂的大脑回路，这些回路是行为和身体重要功能协调的基础。干扰神经元多样性形成的先天性和发育障碍对大脑功能有严重的影响。此外，关于大脑中引起这种多样性的干细胞的知识可能为退行性疾病或损伤后的干预提供强有力的临床方法。这个项目的目标是了解脑干细胞如何根据神经元出生的顺序（时间身份）产生神经元多样性。为了解决这个问题，我们正在使用一个强大的模型系统，果蝇，其中控制时间身份的基因可以被有效地分离出来。我们在这一系统中的研究已经分离出一个基因，称为chinmo（按时间顺序不适当的形态发生），在这一过程中起着核心作用。在这个项目中，我们将阐明Chinmo功能的机制（a）确定它是否是一个通用的时间身份基因，或者是否有其他基因也可以实现这一功能，（B）确定Chinmo功能的机制，（c）寻找其他细胞身份基因，可能与Chinmo功能，或在一个Chinmo独立的方式赋予时间身份。我们希望这些研究将对我们理解神经元多样性是如何产生的，这种神经元多样性是如何在干细胞中编码的，以及如何操纵这些干细胞以产生特定的神经元群体产生根本性的影响。