Molecular characterization of a novel function of the RNA-binding protein Rbfox

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DESCRIPTION (provided by applicant): Post-transcriptional gene regulation has emerged as a critical control mechanism that orchestrates diverse cellular processes during development and adulthood. RNA binding proteins play integral roles in RNA metabolism, regulating a range of processes including splicing and translation. One such family is the RNA-binding fox (Rbfox) proteins, members of which interact with (U)GCAUG elements through a highly conserved RNA-recognition motif. In particular, RBFOX1 has been linked with a number of human disorders ranging from neurological diseases to cancer. The RBFOX1 gene encodes several isoforms: nuclear isoforms that regulate tissue specific alternative splicing and cytoplasmic isoforms, the function of which remains unclear. In the Drosophila germline, Rbfox1 is observed in the cytoplasm and RNAi designed to specifically reduce cytoplasmic Rbfox1 results in impaired germline differentiation. We have shown that Rbfox1 represses translation of transcripts containing (U)GCAUG elements within their 3' UTRs. Excitingly, our results suggest a novel function for an extensively studied splicing regulator and provide the basis for this proposal. The main goal of this proposal is to provide a deeper understanding of the molecular and developmental function of RBFOX1. Our general strategy is to use the sophisticated genetic and molecular tools unique to Drosophila to study Rbfox1 function in vivo. We will take advantage of a Rbfox1 mutant line that we have isolated to genetically investigate the molecular mechanism by which Rbfox1 controls translation. Lastly, we will explore the possibility that cytoplasmic Rbfox1 negatively regulates calcium response within the germline. We anticipate that these efforts will improve our knowledge of the human RBFOX1 function and possibly its role in human pathogenesis.