The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis.
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.
Kimura
Akiko
A
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
MA
Simone
James M
JM
Chen
Weiping
W
Wickre
Mark C
MC
Zhu
Bing-Mei
BM
Hoppe
Philipp S
PS
O'Shea
John J
JJ
Schroeder
Timm
T
Hennighausen
Lothar
L
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000276:immunology; D006098:Granulocytes / Q000166:cytology / Q000276:immunology; D019891:Leukopoiesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D050799:STAT5 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor