Role of microRNAs in T cell development

microRNA 在 T 细胞发育中的作用

• 批准号: 9153781
• 负责人: Alfred Singer
• 金额: $ 24.29万
• 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/9153781
• 关键词: Apoptosis; Apoptotic; Cells; Development; Dicer Enzyme; Equilibrium; Eukaryota; Family; Gene Expression; Generations; Genes; Goals; Knock-out; Messenger RNA; MicroRNAs; Mus; Post-Transcriptional Regulation; Protein Biosynthesis; RNA; RNA Interference; Role; Staging; T-Cell Development; T-Lymphocyte; Thymocyte Development; Thymus Gland; Untranslated RNA; ZNF145 gene; human DICER1 protein; 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干扰是真核生物转录后蛋白表达调控的主要机制之一。这种机制是使用小的非编码rna （miRNAs）来破坏特定mrna的稳定并抑制蛋白质合成。在胸腺发育过程中，许多miRNAs基因在T细胞中表达。然而，RNAi在T细胞发育中的作用尚不清楚。为了研究RNAi在胸腺发育过程中的作用，我们在小鼠中有条件地敲除了Dicer酶，这对miRNA的产生至关重要。我们观察到dicer缺陷小鼠胸腺细胞数量急剧减少，我们确定其原因是胸腺细胞发育过程中从DN到DP阶段的进展受阻。重要的是，我们发现在RNAi缺陷的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缺陷胸腺细胞正在迅速发生凋亡。最重要的是，我们还确定了精确的基因，其表达被microrna下调，从而允许胸腺中发育中的T细胞存活。由于Let7 microrna家族是最大的microrna家族，我们现在研究了Let7家族microrna在胸腺T细胞发育中的作用。我们发现Let7 miRNAs靶向转录因子PLZF，从而调节胸腺内先天样T细胞（即NKT细胞）的分化。