Johnnidis Jonathan B, Harris Marian H, Wheeler Robert T, Stehling-Sun Sandra, Lam Michael H, Kirak Oktay, Brummelkamp Thijn R, Fleming Mark D, Camargo Fernando D
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Nature. 2008 Feb 28;451(7182):1125-9. doi: 10.1038/nature06607. Epub 2008 Feb 17.
MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes. 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.
微小RNA在动物基因组中大量存在，并被预测在广泛的基因表达程序中发挥重要作用。尽管具有这种突出地位，但关于单个哺乳动物微小RNA的功能知识却很匮乏。我们利用小鼠中的功能缺失等位基因，在此报告髓系特异性微小RNA-223（miR-223）对祖细胞增殖以及粒细胞分化和激活具有负调控作用。miR-223（也称为Mirn223）突变小鼠的粒细胞区室扩大，这是由于粒细胞祖细胞数量的细胞自主增加所致。我们表明，促进髓系祖细胞增殖的转录因子Mef2c是miR-223的一个靶点，并且Mef2c的基因敲除抑制了祖细胞扩增，并纠正了miR-223基因敲除小鼠的嗜中性粒细胞表型。此外，缺乏miR-223的粒细胞过度成熟，对激活刺激超敏，并表现出增强的杀真菌活性。由于这种嗜中性粒细胞的过度活跃，miR-223突变小鼠会自发出现炎症性肺部病变，并在内毒素攻击后表现出过度的组织破坏。我们的数据支持这样一种模型，即miR-223作为粒细胞生成和炎症反应的微调器。
