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Regulation of progenitor cell proliferation and granulocyte function by microRNA-223

Authors :
Marian H. Harris
Robert T. Wheeler
Jonathan B. Johnnidis
Sandra Stehling-Sun
Oktay Kirak
Mark D. Fleming
Michael H. Lam
Fernando D. Camargo
Thijn R. Brummelkamp
Source :
Nature. 451(7182)
Publication Year :
2007

Abstract

MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes1,2. 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.

Details

ISSN :
14764687
Volume :
451
Issue :
7182
Database :
OpenAIRE
Journal :
Nature
Accession number :
edsair.doi.dedup.....724f5759563c7acc687e1e825bd574df