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

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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.

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Figure 1: Phenotypic characterization of miR-223 -/Y mice.
Figure 2: Regulation of progenitor cell proliferation by miR-223.
Figure 3: Mef2c is a functional miR-223 target in myeloid progenitors.
Figure 4: Regulation of neutrophil activity and inflammation by miR-223.

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Acknowledgements

We thank D. Bartel and M. Goodell for critical reading of the manuscript, and members of the Bartel and Jaenisch laboratories for discussions. We also thank H. Mulhern, D. Campagna and S. Gokhale for assistance with morphological analysis, and D. Kombe for mouse handling. We are grateful to J. Schwarz for the gift of Mef2c mutant mice. This work was supported by grants from the Whitehead Institute Fellows program.

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA,

    Jonathan B. Johnnidis, Robert T. Wheeler, Sandra Stehling-Sun, Michael H. Lam, Oktay Kirak, Thijn R. Brummelkamp & Fernando D. Camargo

  2. Department of Pathology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Marian H. Harris & Mark D. Fleming

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  1. Jonathan B. Johnnidis
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  2. Marian H. Harris
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  3. Robert T. Wheeler
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  9. Fernando D. Camargo
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Correspondence to Fernando D. Camargo.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S10 with Legends. The Supplementary Figures support the general conclusion that miR-223 fine-tunes the process of granulocyte production and activation. (PDF 1190 kb)

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Johnnidis, J., Harris, M., Wheeler, R. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008). https://doi.org/10.1038/nature06607

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