NEUROLOGICAL FUNCTION OF FRAGILE X GENE IN DROSOPHILA

描述：(改编自申请者的描述)脆性X综合征 是由5‘端未翻译的三重核苷酸CGG扩展引起的 基因FMR1区域，导致基因产物FMRP、a的缺失 与核糖体相关的选择性RNA结合蛋白 神经系统。脆性X研究面临的紧迫挑战是 了解FMRP缺乏引起的细胞发病机制 精神发育迟滞和相关的行为异常。一种潜力 方法是在一个更简单、特征明确的模型中分析FMR1 有机体。 研究人员提议揭开脆性X的突触缺陷 综合征，并鉴定和鉴定新的FMR1相互作用基因 果蝇。他们已经在果蝇中发现了一种FMR1基因同源物，dFXR， 并假设FMR1的功能在果蝇和果蝇之间是保守的 人类。利用强大的果蝇基因，他们提出了 三步法系统研究FMRP的神经功能 接近。特定目标1将产生一系列dFXR突变体，包括 靶向敲除和功能获得突变体的“功能丧失”突变体 通过操纵转基因的表达。特定目标2将 描述dFXR的神经功能，重点是突触 发育、功能和可塑性。《特定目标3》将搜索小说 DFXR与基因增强子/抑制子相互作用的基因筛选和 微阵列技术。因此，此应用程序补充并扩展了 对哺乳动物系统的平行研究。

DESCRIPTION: (Adapted from the applicant's Description) Fragile X syndrome is caused by a triplet nucleotide CGG expansion within the 5' untranslated region in the gene FMR1, resulting in the absence of the gene product, FMRP, a selective RNA-binding protein associated with ribosomes and enriched in nervous system. The compelling challenge in fragile X research is to understand the cellular pathogenesis by which the lack of FMRP gives rise to mental retardation and associated behavioral abnormalities. One potential approach is to assay the FMR1 within a simpler, well-characterized model organism. The investigators propose to uncover the synaptic defects of fragile X syndrome, and identify and characterize novel FMR1 interacting genes in Drosophila. They have identified a FMR1 gene homologue in Drosophila, dFXR, and hypothesized that the function of FMR1 is conserved between Drosophila and human. Taking advantage of powerful Drosophila genetics, they propose to systemically investigate the neurological functions of FMRP by a three-step approach. Specific Aim 1 will generate a series of dFXR mutants, including "loss of function" mutants by targeted knockout and "gain of function" mutants by manipulating the expression of transgenes. Specific Aim 2 will characterize the neurological functions of dFXR, focusing on synaptic development, function, and plasticity. Specific Aim 3 will search for novel dFXR interacting genes with a genetic enhancer / suppressor screening and microarray technology. This application therefore complements and extends the parallel studies on mammalian systems.