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

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.

Pubmed ID: 18278031

Authors

  • Johnnidis JB
  • Harris MH
  • Wheeler RT
  • Stehling-Sun S
  • Lam MH
  • Kirak O
  • Brummelkamp TR
  • Fleming MD
  • Camargo FD

Journal

Nature

Publication Data

February 28, 2008

Associated Grants

None

Mesh Terms

  • Alleles
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Gene Deletion
  • Granulocytes
  • Inflammation
  • Lung
  • MEF2 Transcription Factors
  • Mice
  • Mice, Knockout
  • MicroRNAs
  • Myogenic Regulatory Factors
  • Neutrophils
  • Phenotype
  • Stem Cells