Dissecting the Molecular Basis of Fragile X Syndrome in Drosophila

Emory University, Atlanta GA

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Abstract

Fragile X syndrome, a common form of inherited mental retardation, is caused by the loss of the fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein that forms a messenger ribonucleoprotein (mRNP) complex associating with polyribosomes. Evidence suggests that FMRP is involved in local regulation of protein synthesis at synapses. The loss of FMRP leads to abnormal translation of selective mRNAs, delayed maturation of dendritic spines, abnormal microtubule stability and abnormal behavioral phenotypes. Since the Drosophila model allows powerful genetic and molecular manipulation, the last several years have seen the increasing use of the fruit fly as a model system to study this disorder. Phenotypic analyses have demonstrated an array of neuronal and behavioral defects in fruit fly that are similar to the phenotypes reported in mouse models as well as in human patients. MicroRNAs (miRNAs) are 18- to 25-nucleotide (nt), small noncoding regulatory RNAs that are known to regulate translation of target mRNA molecules in a sequence-specific manner. Several lines of evidence, including ours, suggest that FMRP could potentially utilize the miRNA pathway to regulate the translation of its mRNA targets, hence modulate cellular and behavioral phenotypes. By combining immunoprecipitation with miRNA TaqMan assays and deep sequencing, we have now identified specific miRNAs associated with dFmrp in fly brain. Furthermore, given the role of FMRP and miRNAs in translational regulation, we have developed a high-throughput proteomic analyses using metabolically labeled fly, which enable us to perform proteomic analyses on the mutants of dFmr1 and dFmrp-associated miRNAs. In this competing renewal application, we plan to further decipher the functional importance of the interaction between dFmrp and the miRNA pathway, particularly the role of specific miRNAs associated with dFmrp, in neural development as well as learning and memory using Drosophila as a model system. The success of the proposed work should advance our knowledge on how the loss of FMRP leads to the misregulated translation of its mRNA targets, and the clinical phenotype of FXS as well as potential common pathogenic pathway(s) underlying autism.