Abstract
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/EBPα 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.
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Change history
15 September 2003
appended AOP PDF with erratum (will be corrected for print issue) and placed footnote in SGML where references to Fig. 4a occur
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Acknowledgements
We acknowledge S. Reiner and K.C. Dahl for critically reading the manuscript. We thank the following for providing reagents: W. Pear, M. Lazar, R. Feldman and N. Berliner. This work was supported by the Abramson Family Cancer Research Institute (R.D. and M.C.S.) and the Howard Hughes Medical Institute (R.D., D.L., P.L., S.R.I., H.S. and M.C.S.), and National Institutes of Health grants 5RO1HL052094 (M.C.S.), 5T32GM07151 (J.C.W.) and 5T32HL07237 (J.C.W.) M.C.S. and H.S. are investigators of the Howard Hughes Medical Institute.
*Note: In the version of this article originally published online, the label for Figure 4a was incorrect. It should read PU.1-/-. This error has been corrected for the HTML and print versions of the article.
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Dahl, R., Walsh, J., Lancki, D. et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPα ratio and granulocyte colony-stimulating factor. Nat Immunol 4, 1029–1036 (2003). https://doi.org/10.1038/ni973
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DOI: https://doi.org/10.1038/ni973
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