NEUROLOGICAL FUNCTION OF FRAGILE X GENE IN DROSOPHILA

描述：（改编自申请人的描述）脆性X综合征 是由5'非翻译区内的三联核苷酸CGG扩增引起的。 基因FMR 1中的区域，导致基因产物FMRP，a 与核糖体相关的选择性RNA结合蛋白， 神经系统 脆性X染色体研究中最大的挑战是 了解缺乏FMRP引起的细胞发病机制， 精神发育迟缓和相关的行为异常。 一个潜在 一种方法是在一个更简单的，充分表征的模型中测定FMR 1 有机体 研究人员建议揭示脆性X染色体的突触缺陷， 综合征，并确定和表征新的FMR 1相互作用基因， 果蝇 他们在果蝇中发现了FMR 1基因同源物dFXR， 并假设FMR 1的功能在果蝇和果蝇之间是保守的， 人类 利用果蝇强大的遗传学，他们提出， 分三步系统研究FMRP的神经功能 approach. 特异性Aim 1将产生一系列dFXR突变体，包括 通过靶向敲除的“功能丧失”突变体和“功能获得”突变体 通过操纵转基因的表达。 具体目标2将 表征dFXR的神经功能，重点是突触 发育、功能和可塑性。 Specific Aim 3将搜索新的 用遗传增强子/抑制子筛选dFXR相互作用基因， 微阵列技术 因此，本申请补充并扩展了 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.