Control of Dendritic Development by FMR1

FMR1 控制树突发育

• 批准号: 7038384
• 负责人: Fen-Biao Gao
• 金额: $ 33.75万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038384
• 关键词: Drosophilidae; RNA binding protein; arthropod genetics; dendrites; developmental neurobiology; fragile X syndromes; gene dosage; gene mutation; genetic mapping; genetic translation; larva; morphometry; mutant; neural plasticity; neurogenesis; neurogenetics; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): The nervous system is composed of a vast number of neurons that vary dramatically in size and shape. Neurons are highly polarized cells with distinct subcellular compartments, including one or more dendritic processes arising from the cell body and a single, extended axon. Elucidating the mechanisms that control neuronal polarity and dendritic development is of critical importance for understanding the development and plasticity of a functional nervous system. In addition, alternations in the number of dendritic branches and dendritic spines are often found in patients with neurological disorders, such as fragile X syndrome. Fragile X syndrome is the most common form of inherited mental retardation in humans, with an estimated incidence of 1 in 4000 males and 1 in 8000 females. The disorder is caused by the loss of the fragile X mental retardation 1 (fmr1) gene activity. FMR1 is an RNA-binding protein that contains two ribonucleoprotein K homology domains (KH domains) and an arginine- and glycine-rich domain (RGG box). The physiological function of FMR1 in neural development remains largely unknown. The long-term goal of this laboratory is to understand the molecular mechanisms underlying dendritic outgrowth, branching, and remodeling during development. The peripheral nervous system (PNS) of the fruitfly Drosophila is an ideal model system for these studies. PNS neurons can be individually identified, and their dendritic morphology can be studied in real time in living animals. A large number of genes identified in PNS also affect dendritic development of central nervous system (CNS) neurons. In addition, the Drosophila model allows powerful genetic and molecular manipulations. Recently, we have generated specific mutations in the Drosophila fmr1 (dfmr1) gene. Our preliminary studies indicate that dfmr1 mutations primarily affect the formation of higher-order dendritic branches. In this proposal, we will carry out a series of experiments to further understand how FMR1 controls dendritic development. Specially, (1) we will further characterize the dendritic overextension phenotype caused by dfmr1 mutations, (2) we will investigate how dFMR1 functions at the mechanistic level, and (3) we will use genetic approaches to identify other proteins that also control dendritic development and may interact with dFMR1. Molecular mechanisms underlying many biological processes are highly conserved throughout evolution. Studies of the mechanisms that control dendritic development in Drosophila may help us understand similar processes in human brains. The insights gained from these studies may also contribute to our understanding of fragile X syndrome.

描述(由申请人提供)： 神经系统由大量大小和形状迥异的神经元组成。神经元是高度极化的细胞，具有不同的亚细胞间隔，包括一个或多个来自细胞体的树突状突起和单个延伸的轴突。阐明控制神经元极性和树突发育的机制对于了解功能神经系统的发育和可塑性至关重要。此外，在患有脆性X综合征等神经疾病的患者中，树突状分支和树突棘的数量经常发生变化。脆性X综合征是人类最常见的遗传性智力低下形式，估计发病率为每4000名男性和每8000名女性中就有一名。这种疾病是由脆性X智力低下1(Fmr1)基因活性丧失引起的。FMR1是一种RNA结合蛋白，含有两个核糖核蛋白K同源结构域(KH结构域)和一个富含精氨酸和甘氨酸的结构域(RGG Box)。FMR1在神经发育中的生理功能在很大程度上仍然未知。这个实验室的长期目标是了解树突生长、分支和发育过程中重塑的分子机制。果蝇的外周神经系统(PNS)是进行这些研究的理想模型系统。三叉神经节神经元可以单独鉴定，其树突形态可以在活体动物中实时研究。在三叉神经节中发现的大量基因也影响中枢神经系统(CNS)神经元的树突发育。此外，果蝇模型允许进行强大的遗传和分子操作。最近，我们在果蝇fmr1(Dfmr1)基因上产生了特定的突变。我们的初步研究表明，dfmr1突变主要影响更高阶树突状分支的形成。在这项提案中，我们将进行一系列实验，以进一步了解FMR1是如何控制树突发育的。特别是，(1)我们将进一步表征由dfmr1突变引起的树突状细胞过度伸展表型，(2)我们将从机制水平上研究dFMR1是如何发挥作用的，以及(3)我们将使用遗传学方法来鉴定其他也控制树突状细胞发育并可能与dFMR1相互作用的蛋白质。在整个进化过程中，许多生物过程背后的分子机制是高度保守的。对果蝇树突发育控制机制的研究可能有助于我们理解人类大脑中类似的过程。从这些研究中获得的见解也可能有助于我们对脆性X综合征的理解。