Fragile X syndrome is caused by the lack of the functional protein product encoded by the FMR1 gene, designated as FMRP. Although the exact function of FMRP remains to be defined, accumulating evidence supports the concept that FMRP is a messenger-ribonucleoprotein (mRNP), which selectively associates with translating polyribosomes via poly-A RNA in living cells. The functional importance of FMRP-polyribosome association and mRNP complex formation has been indicated by the fact that the 1304N point mutation, identified from an unusually severe fragile X patient, causes incorporation of FMRP into abnormal mRNP particles that fail to associate with polyribosomes. These observations have led the applicant to hypothesize that FMRP interacts with its mRNA targets within the mRNP complexes and controls the translation activity of these mRNAs. This hypothesis is reinforced by the applicant?s recent finding that FMRP inhibits translation in vitro in a dose-dependent and mRNA-selective manner. This proposal aims to further test the above hypothesis using in vitro translation systems, cultured cell lines, as well as wild type and fmrl knockout neurons by the following three specific aims: 1). To test the hypothesis that the selectivity of FMRP as a translation suppresser in the rabbit reticulocyte lysate (RRL) is determined by the FMRP-binding activity of the translation templates; 2). To elucidate possible mechanisms for the in vitro translation inhibition caused by FMRP; 3). To test the hypothesis that FMRP inhibits translation in living cells, and extracellular signals modulates FMRP?s influence on translation. The proposed research will address how FMRP may influence translation, and whether FMRP?s influence on translation can be regulated to accommodate cell function. Answers to these questions should greatly improve our knowledge on FMRP?s function, which not only facilitates the elucidation of the pathogenesis of fragile X syndrome, but more importantly helps to understand how RNA-protein interactions may regulate translation to impact brain function and development.
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