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.
Johnnidis
Jonathan B
JB
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Harris
Marian H
MH
Wheeler
Robert T
RT
Stehling-Sun
Sandra
S
Lam
Michael H
MH
Kirak
Oktay
O
Brummelkamp
Thijn R
TR
Fleming
Mark D
MD
Camargo
Fernando D
FD
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D017353:Gene Deletion; D006098:Granulocytes / Q000166:cytology* / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000473:pathology; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology*
D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors