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.
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
Akiko
A
Kimura
Michael A
MA
Rieger
James M
JM
Simone
Weiping
W
Chen
Mark C
MC
Wickre
Bing-Mei
BM
Zhu
Philipp S
PS
Hoppe
John J
JJ
O'Shea
Timm
T
Schroeder
Lothar
L
Hennighausen
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