Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor.
Hematopoietic transcription factors are essential for specifying cell fates; however, the function of cytokines in such developmental decisions is unresolved. We demonstrate here that haploinsufficiency for the gene encoding the transcription factor PU.1 partially suppresses the neutropenia of mice deficient in granulocyte colony-stimulating factor. This suppression was due to an increase in granulocytic progenitors and a diminution of monocytic progenitors. With (PU.1+/-) ES cells as well as (PU.1-/-) hematopoietic progenitors, we show that higher expression of PU.1 is needed for macrophage than for neutrophil development. In a (PU.1-/-) progenitor cell line, in which graded activity of PU.1 regulates neutrophil versus macrophage development, granulocyte colony-stimulating factor signaling supported the neutrophil cell fate by increasing expression of the neutrophil transcription factor C/EBPalpha in relation to expression of PU.1. Collectively, these results indicate that cytokines can promote cell fate decisions by altering the relative concentrations of lineage-determining transcriptional regulators.
Dahl
Richard
R
Howard Hughes Medical Institute, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Walsh
Jonathan C
JC
Lancki
David
D
Laslo
Peter
P
Iyer
Sangeeta R
SR
Singh
Harinder
H
Simon
M Celeste
MC
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D003114:Colony-Forming Units Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D037021:Thyroid Hormone Receptors alpha; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1