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

Jonathan B. Johnnidis, Marian H. Harris, Robert T. Wheeler, Sandra Stehling-Sun, Michael H. Lam, Oktay Kirak, Thijn R. Brummelkamp, Mark D. Fleming and Fernando D. Camargo ()
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Jonathan B. Johnnidis: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Marian H. Harris: Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Robert T. Wheeler: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Sandra Stehling-Sun: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Michael H. Lam: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Oktay Kirak: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Thijn R. Brummelkamp: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Mark D. Fleming: Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Fernando D. Camargo: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA

Nature, 2008, vol. 451, issue 7182, 1125-1129

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature06607

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