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

描述（由申请人提供）：转录后基因调控已成为一种关键的控制机制，在发育和成年期间协调多种细胞过程。RNA结合蛋白在RNA代谢中发挥着不可或缺的作用，调控着包括剪接和翻译在内的一系列过程。其中一个家族是rna结合狐狸（Rbfox）蛋白，其成员通过高度保守的rna识别基序与(U)GCAUG元件相互作用。特别是，RBFOX1与从神经系统疾病到癌症的许多人类疾病有关。RBFOX1基因编码几种异构体：调节组织特异性选择性剪接的核异构体和功能尚不清楚的细胞质异构体。在果蝇种系中，Rbfox1在细胞质中被观察到，旨在特异性减少细胞质Rbfox1的RNAi导致种系分化受损。我们已经证明Rbfox1在其3' utr内抑制含有(U)GCAUG元件的转录本的翻译。令人兴奋的是，我们的研究结果为广泛研究的剪接调节因子提供了一种新的功能，并为这一提议提供了基础。这个

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.