Role of microRNAs in T cell development

microRNA 在 T 细胞发育中的作用

• 批准号: 10702475
• 负责人: Alfred Singer
• 金额: $ 38.68万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702475
• 关键词: Apoptosis; Apoptotic; Cells; Development; Dicer Enzyme; Equilibrium; Eukaryota; Family; Gene Expression; Generations; Genes; Goals; Messenger RNA; MicroRNAs; Mus; Post-Transcriptional Regulation; Protein Biosynthesis; RNA; RNA Interference; Role; T-Cell Development; T-Lymphocyte; Thymocyte Development; Thymus Gland; Untranslated RNA; ZNF145 gene; conditional knockout; protein expression; thymocyte; transcription factor

RNA intererence is a one of the major mechanisms of post-transcriptional regulation of protein expression in eukaryotes. This mechanism is using small non-coding RNAs (miRNAs) to destabilize specific mRNAs and to suppress protein synthesis. Many miRNAs genes are expressed in T cells during development in a thymus. However the function of RNAi in T cell development remains unclear. To investigate the role of RNAi during thymic development we generated conditional knockout of the enzyme Dicer in the mouse, which is critical for miRNA generation. We observed a dramatic reduction in the number of thymocytes in Dicer-deficient mice and we determined that the reason is a block of progression from DN to DP stage during thymocyte development. Importantly, we found an alteration in the balance between pro- and anti-apoptotic factors in RNAi deficient DP thymocytes. We also observed that RNAi-deficient thymocytes are rapidly undergoing apoptosis. Most importantly, we have also identified the precise gene whose expression is downregulated by microRNAs to permit survival of developing T cells in the thymus. Because the Let7 family of microRNAs is the largest miRNA family, we have now examined the role of Let7 family microRNAs in T cell development in the thymus. We found that Let7 miRNAs target the transcription factor PLZF and so regulate the differentiation of innate-like T cells (i.e. NKT cells) in the thymus.

RNA相互关系是真核生物中蛋白质表达的转录后调节的主要机制之一。该机制使用小的非编码RNA（miRNA）来破坏特定的mRNA并抑制蛋白质合成。在胸腺发育过程中，许多miRNA基因在T细胞中表达。但是，RNAi在T细胞发育中的功能尚不清楚。为了研究RNAi在胸腺发育过程中的作用，我们在小鼠中产生了条件敲除酶dicer的条件敲除，这对于miRNA的产生至关重要。 我们观察到dicer缺乏小鼠的胸腺细胞数量显着减少，我们确定原因是胸腺细胞发育过程中从DN到DP阶段的进展块。重要的是，我们发现RNAi缺乏DP胸腺细胞中促凋亡因子和抗凋亡因子之间的平衡发生了变化。我们还观察到RNAi缺陷型胸腺细胞正在迅速凋亡。最重要的是，我们还确定了精确的基因，其表达被microRNA下调以允许胸腺中发育细胞的存活。由于MicroRNA的LET7家族是最大的miRNA家族，因此我们现在研究了LET7家族microRNA在胸腺中T细胞发育中的作用。我们发现让7 miRNA靶向转录因子PLZF，因此调节了胸腺中先天样T细胞（即NKT细胞）的分化。