Control of Dendritic Development by FMR1

描述（由申请人提供）： 神经系统由大量的神经元组成，这些神经元在大小和形状上变化很大。神经元是高度极化的细胞，具有不同的亚细胞区室，包括从细胞体产生的一个或多个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理解功能性神经系统的发育和可塑性至关重要。此外，树突分支和树突棘数量的变化经常在神经系统疾病患者中发现，如脆性X综合征。脆性X染色体综合征是人类遗传性智力低下的最常见形式，估计发病率为1/4000男性和1/8000女性。这种疾病是由脆性X智力低下1（fmr 1）基因活性的丧失引起的。FMR 1是一种RNA结合蛋白，包含两个核糖核蛋白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盒）。FMR 1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发育过程中树突状生长、分支和重塑的分子机制。果蝇的外周神经系统是进行这些研究的理想模型系统。PNS神经元可以单独识别，并且可以在活体动物中真实的时间研究它们的树突形态。在PNS中鉴定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，果蝇模型允许强大的遗传和分子操纵。最近，我们在果蝇fmr 1（dfmr 1）基因中产生了特定的突变。我们的初步研究表明，dfmr 1突变主要影响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FMR 1如何控制树突发育。特别是，（1）我们将进一步表征dfmr 1突变引起的树突状细胞过度伸展表型，（2）我们将研究dFMR 1如何在机制水平上发挥作用，（3）我们将使用遗传方法来鉴定其他蛋白质，这些蛋白质也控制树突状细胞的发育，并可能与dFMR 1相互作用。许多生物过程的分子机制在整个进化过程中是高度保守的。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。

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.