ZFC3H1介导的RNA核内降解在小鼠精子发生中的功能和机制研究

RNA降解是确保遗传信息精准传递的重要机制，进化上高度保守的RNA外切体是最主要的RNA降解机器。以往关于RNA降解的研究多集中于细胞质中，而关于核内降解的机制和功能的理解还非常粗浅。ZFC3H1-MTR4复合体是RNA外切体在细胞核内重要的辅助因子，主要负责降解带有多聚腺苷酸尾的底物RNA。精子发生过程伴随剧烈的基因表达调控，大量的mRNA需要在此过程中被快速清除。ZFC3H1-MTR4复合体在球形精子中特异性高表达，然而其介导的RNA核内降解是否以及如何影响精子发生并不清楚。在本项目中，我们将综合利用分子细胞生物学、发育生物学、转录组学和生物信息学等手段，系统研究ZFC3H1-MTR4复合体的形成和招募机制，探索其在小鼠精子发生过程中的功能，并阐明其功能发挥的分子机制。这些研究将在整体动物水平揭示RNA核内降解的功能机制，并为雄性不育的诊治提供新的思路和策略。

RNA degradation is an important mechanism for ensuring precise expression of genetic information. The evolutionarily highly conserved exosome complex is the central RNA degradation machine. Previous studies have been mainly focused on RNA degradation in the cytoplasm, and the mechanisms and functions of nuclear RNA degradation remain largely unknown. The ZFC3H1-MTR4 complex, a key nuclear exosome cofactor, is responsible for exosomal degradation of polyadenylated RNAs. During spermatogenesis, gene expression is dramatically regulated and massive RNA degradation occurs. ZFC3H1-MTR4 is highly expressed in round spermatid. However, how nuclear RNA degradation mediated by this complex is involved in spermatogenesis remains unknown. In this project, we plan to utilize molecular and cellular biological, developmental biological, transcriptomic and bioinformatics methods to systematically determine the formation and recruitment mechanism of the ZFC3H1-MTR4 complex, study the functional relevance of ZFC3H1 in mouse spermatogenesis, and investigate the underlying mechanism(s). These studies will reveal the biological relevance of nuclear RNA degradation at the animal level, and provide important insights into the diagnosis and therapy of male sterility.