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PMID: 19779039 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis.

Blood ·Vol. 114 ·No. 21 ·2009-11-19 ·Pages 4721-8

Kimura A, Rieger MA, Simone JM, Chen W, Wickre MC, Zhu BM, Hoppe PS, O'Shea JJ, Schroeder T, Hennighausen L

Abstract

Neutrophils play a vital role in the immune defense, which is evident by the severity of neutropenia causing life-threatening infections. Granulocyte macrophage-colony stimulating factor (GM-CSF) controls homeostatic and emergency development of granulocytes. However, little is known about the contribution of the downstream mediating transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A/B). To elucidate the function of this pathway, we generated mice with complete deletion of both Stat5a/b genes in hematopoietic cells. In homeostasis, peripheral neutrophils were markedly decreased in these animals. Moreover, during emergency situations, such as myelosuppression, Stat5a/b-mutant mice failed to produce enhanced levels of neutrophils and were unable to respond to GM-CSF. Both the GM-CSF-permitted survival of mature neutrophils and the generation of granulocytes from granulocyte-macrophage progenitors (GMPs) were markedly reduced in Stat5a/b mutants. GMPs showed impaired colony-formation ability with reduced number and size of colonies on GM-CSF stimulation. Moreover, continuous cell fate analyses by time-lapse microscopy and single cell tracking revealed that Stat5a/b-null GMPs showed both delayed cell-cycle progression and increased cell death. Finally, transcriptome analysis indicated that STAT5A/B directs GM-CSF signaling through the regulation of proliferation and survival genes.

MeSH Terms
Animals Bone Marrow Cells/cytology,immunology Cell Proliferation Enzyme-Linked Immunosorbent Assay Flow Cytometry Gene Expression Gene Expression Profiling Gene Expression Regulation/immunology Granulocyte-Macrophage Colony-Stimulating Factor/immunology Granulocyte-Macrophage Progenitor Cells/cytology,immunology Granulocytes/cytology,immunology Leukopoiesis/physiology Mice Mice, Knockout Neutrophils/cytology,immunology Oligonucleotide Array Sequence Analysis STAT5 Transcription Factor/immunology Signal Transduction/immunology
Chemicals
STAT5 Transcription Factor Stat5a protein, mouse Stat5b protein, mouse Granulocyte-Macrophage Colony-Stimulating Factor
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Kimura Akiko
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
Rieger Michael A
Simone James M
Chen Weiping
Wickre Mark C
Zhu Bing-Mei
Hoppe Philipp S
O'Shea John J
Schroeder Timm
Hennighausen Lothar
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2009-04-216390
Published
2009-11-19
Epub
2009-00-24
Pages
4721-8
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2780307
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1182/blood-2009-04-216390 PMC Full Text View journal details
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