Regulation of progenitor cell proliferation and granulocyte function by microRNA-223
Regulation of progenitor cell proliferation and granulocyte function by microRNA-223
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DOI：
10.1038/nature06607
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发表时间：
2008-02-28
期刊：
影响因子：
64.8
通讯作者：
Camargo, Fernando D.
中科院分区：
文献类型：
--
作者：
Johnnidis, Jonathan B.;Harris, Marian H.;Camargo, Fernando D.
microrna在动物基因组中含量丰富，并被预测在广泛的基因表达程序中发挥重要作用（1,2）。尽管如此，关于单个哺乳动物microrna的功能知识仍然缺乏。在小鼠中使用功能缺失等位基因，我们在这里报告了髓系特异性microRNA- 223 （miR- 223）负调控祖细胞增殖和粒细胞分化和活化。miR- 223（也称为Mirn223）突变小鼠由于粒细胞祖细胞数量的细胞自主增加而具有扩大的粒细胞室。我们发现Mef2c，一种促进髓系祖细胞增殖的转录因子，是miR- 223的靶标，并且Mef2c的基因消融抑制了miR- 223缺失小鼠的祖细胞扩增并纠正了中性粒细胞表型。此外，缺乏miR- 223的粒细胞是超成熟的，对激活刺激超敏感，并显示出增加的杀真菌活性。由于这种中性粒细胞过度活跃，miR- 223突变小鼠在内毒素攻击后会自发地发生炎症性肺病理，并表现出夸大的组织破坏。我们的数据支持miR- 223作为粒细胞产生和炎症反应的微调器的模型。
MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes(1,2). Despite this prominence, there is a dearth of functional knowledge regarding individual mammalian microRNAs. Using a loss- of- function allele in mice, we report here that the myeloid- specific microRNA- 223 ( miR- 223) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR- 223 ( also called Mirn223) mutant mice have an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. We show that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR- 223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR- 223 null mice. In addition, granulocytes lacking miR- 223 are hypermature, hypersensitive to activating stimuli and display increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR- 223 mutant mice spontaneously develop inflammatory lung pathology and exhibit exaggerated tissue destruction after endotoxin challenge. Our data support a model in which miR- 223 acts as a fine- tuner of granulocyte production and the inflammatory response.