Rbm24介导的细胞质多腺苷酸化调节成肌细胞分化的机制研究

RNA结合蛋白介导的转录后调控对促进细胞分化及维持组织稳态有关键作用。Rbm24在脊椎动物胚胎的表达图式高度保守并参与骨骼肌和心肌的发育，但其作用机制还需深入的系统性研究。我们发现该蛋白在肌细胞分化过程中呈动态的亚细胞定位，且在进入分化程序的细胞中仅分布于细胞质。Rbm24缺失突变体中，mRNA的多腺苷酸尾显著缩短、稳定性和翻译效率严重降低。生化分析显示Rbm24可能是细胞质多腺苷酸化复合物的一个新成员。基于这些原创性工作基础，本项目拟探索Rbm24如何通过调节细胞质多腺苷酸化而促进肌细胞分化这一科学问题。我们将利用斑马鱼模型，在肌细胞分化过程中鉴定Rbm24调节的mRNA多腺苷酸化事件、阐明其与细胞质多腺苷酸化复合物的互作方式、揭示肌细胞分化的转录后调控机制。本研究的预期成果将为我们认识细胞质多腺苷酸化在发育中的调节性功能提供新视野，同时也可能为肌细胞分化缺陷相关的人类疾病提供潜在靶点。

Post-transcriptional regulation of gene expression orchestrated by RNA-binding proteins (RBPs) plays critical roles in promoting cell differentiation and tissue homeostasis during development. Mutations or dysfunctions of RBPs cause various neuromuscular diseases in humans. The expression pattern of Rbm24 is highly conserved in vertebrate embryos. Analyses of Rbm24 function indicate that it plays an important role in skeletal and cardiac muscle development, but the regulatory mechanism remains elusive. Our recent works have made the unprecedented finding that Rbm24 displays very dynamic subcellular localization during muscle cell differentiation. In all tissues examined, it is exclusively localized in the cytoplasm of a population of cells engaged in the differentiation program, which is not consistent with a role in alternative splicing that takes place in the nucleus. Furthermore, loss of Rbm24 function causes shortening of the poly(A) tail length in differentiation-related mRNAs, and as a consequence, leads to reduced stability and translation efficiency. Importantly, we find that Rbm24 interacts with the cytoplasmic polyadenylation complex, implying that it may represent a novel regulator of cytoplasmic polyadenylation. Based on these original results, this project plans to investigate how Rbm24 promotes muscle cell differentiation through regulation of cytoplasmic polyadenylation. We will use zebrafish as a model to identify target mRNAs regulated by Rbm24, and to elucidate the mechanism by which it interacts with cytoplasmic polyadenylation complex and promotes differentiation-related protein accumulation during myogenesis. The expected results should provide mechanistic insight into the regulatory and tissue-specific function of cytoplasmic polyadenylation in controlling key developmental processes. Given the growing number of diseases associated with RNAs and RBPs, this work also presents the potential to be translated into new therapeutic avenues for the treatment of human diseases associated with muscle cell differentiation defects.