Publication Date:
2008-02-19
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- England -- Nature. 2008 Feb 28;451(7182):1125-9. doi: 10.1038/nature06607. Epub 2008 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18278031" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Animals
;
Cell Differentiation
;
*Cell Proliferation
;
Gene Deletion
;
Granulocytes/*cytology/immunology/pathology/*physiology
;
Inflammation/genetics/immunology/pathology
;
Lung/pathology
;
MEF2 Transcription Factors
;
Mice
;
Mice, Knockout
;
MicroRNAs/*genetics/*metabolism
;
Myogenic Regulatory Factors/genetics/metabolism
;
Neutrophils/physiology
;
Phenotype
;
Stem Cells/*cytology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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