DOI: 10.1073/pnas.94.2.569. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice

Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice

10.1073/pnas.94.2.569

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Transcription factors are master regulatory switches of differentiation, including the development of specific hematopoietic lineages from stem cells. Here we show that mice with targeted disruption of the CCAAT enhancer binding protein α gene (C/EBPα) demonstrate a selective block in differentiation of neutrophils. Mature neutrophils and eosinophils are not observed in the blood or fetal liver of mutant animals, while other hematopoietic lineages, including monocytes, are not affected. Instead, most of the white cells in the peripheral blood of mutant mice had the appearance of myeloid blasts. We also observed a selective loss of expression of a critical gene target of CCAAT enhancer binding protein α, the granulocyte colony-stimulating factor receptor. As a result, multipotential myeloid progenitors from the mutant fetal liver are unable to respond to granulocyte colony-stimulating factor signaling, although they are capable of forming granulocyte–macrophage and macrophage colonies in methylcellulose in response to other growth factors. Finally, we demonstrate that the lack of granulocyte development results from a defect intrinsic to the hematopoietic system; transplanted fetal liver from mutant mice can reconstitute lymphoid but not neutrophilic cells in irradiated recipients. These studies suggest a model by which transcription factors can direct the differentiation of multipotential precursors through activation of expression of a specific growth factor receptor, allowing proliferation and differentiation in response to a specific extracellular signal. In addition, thec/ebpα−/−mice may be useful in understanding the mechanisms involved in acute myelogenous leukemia, in which a block in differentiation of myeloid precursors is a key feature of the disease.

Bibliography

Zhang, D.-E., Zhang, P., Wang, N., Hetherington, C. J., Darlington, G. J., & Tenen, D. G. (1997). Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding proteinâÎ±-deficientâmice. Proceedings of the National Academy of Sciences, 94(2), 569â574.

Authors 6

Dong-Er Zhang (first)
Pu Zhang (additional)
Nai-dy Wang (additional)
Christopher J. Hetherington (additional)
Gretchen J. Darlington (additional)
Daniel G. Tenen (additional)

References 63 Referenced 775

10.1182/blood.V87.10.4025.bloodjournal87104025
10.1002/stem.5530130304
10.1182/blood.V80.12.2953.2953
10.1016/1040-8428(92)90088-8
10.1097/00062752-199502010-00002
10.1126/science.3289117
10.1101/gad.1.2.133
10.1101/gad.2.7.786
10.1073/pnas.85.11.3840
10.1101/gad.3.9.1314
10.1101/gad.3.9.1323
10.1101/gad.5.9.1538
10.1073/pnas.91.19.8757
10.1126/science.7652557
10.1101/gad.5.9.1553
10.1002/j.1460-2075.1990.tb08316.x
10.1002/j.1460-2075.1995.tb07319.x
10.1101/gad.4.8.1416
10.1002/j.1460-2075.1995.tb00106.x
J G Haas, M Strobel, A Leutz, P Wendelgass, C Muller, E Sterneck, G Riethmuller, H W Ziegler-Heitbrock J Immunol 149, 237–243 (1992). (10.4049/jimmunol.149.1.237) / J Immunol by Haas J G (1992)
10.1002/j.1460-2075.1992.tb05034.x
10.1101/gad.7.5.749
10.1002/j.1460-2075.1993.tb05777.x
10.1101/gad.5.10.1754
10.1128/mcb.14.11.7285-7297.1994
10.1016/0092-8674(95)90418-2
10.1002/j.1460-2075.1995.tb07185.x
10.1182/blood.V80.7.1725.1725
10.1182/blood.V79.2.460.460
10.1182/blood.V88.4.1234.bloodjournal8841234
10.1128/MCB.15.10.5830
10.1128/MCB.16.3.1231
10.1128/MCB.16.9.4717
10.1073/pnas.93.20.10838
D-E Zhang, C J Hetherington, D A Gonzalez, H M Chen, D G Tenen J Immunol 153, 3276–3284 (1994). (10.4049/jimmunol.153.7.3276) / J Immunol by Zhang D-E (1994)
10.1182/blood.V86.8.2876.2876
10.1002/eji.1830090410
K Hestdal, F W Ruscetti, J N Ihle, S E W Jacobsen, C M Dubois, W C Kopp, D L Longo, J R Keller J Immunol 147, 22–28 (1991). (10.4049/jimmunol.147.1.22) / J Immunol by Hestdal K (1991)
D-E Zhang, S Hohaus, M T Voso, H M Chen, L T Smith, C J Hetherington, D G Tenen Curr Top Microbiol Immunol 211, 137–147 (1996). / Curr Top Microbiol Immunol by Zhang D-E (1996)
10.1182/blood.V82.12.3515.3515
10.1182/blood.V75.1.1.bloodjournal7511
10.3109/08977199309046930
10.1016/0092-8674(90)90814-U
10.1016/0092-8674(89)90965-3
10.1182/blood.V80.5.1183.1183
V M Rothwell, L R Rohrschneider Oncog Res 1, 311–324 (1987). / Oncog Res by Rothwell V M (1987)
10.1182/blood.V78.11.2791.bloodjournal78112791
10.1182/blood.V88.3.761.bloodjournal883761
10.1182/blood.V75.3.563.563
10.1182/blood.V81.4.916.916
F W Shen, J S Tung, E A Boyse Immunogenetics 24, 146–149 (1986). (10.1007/BF00364741) / Immunogenetics by Shen F W (1986)
10.1007/BF01564083
10.1073/pnas.91.17.7932
10.1126/science.8079170
10.1002/j.1460-2075.1996.tb00949.x
10.1182/blood.V88.8.2917.bloodjournal8882917
10.1016/0092-8674(95)90234-1
10.1002/j.1460-2075.1992.tb05557.x
10.1101/gad.9.10.1250
10.1128/mcb.14.12.8085-8095.1994
10.1073/pnas.93.23.13158
10.1182/blood.V84.6.1737.1737
10.1016/S1074-7613(00)80504-X

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:35 a.m.)
Deposited	1 year, 7 months ago (Jan. 3, 2024, 11:52 p.m.)
Indexed	1 week, 3 days ago (Aug. 23, 2025, 12:58 a.m.)
Issued	28 years, 7 months ago (Jan. 21, 1997)
Published	28 years, 7 months ago (Jan. 21, 1997)
Published Online	28 years, 7 months ago (Jan. 21, 1997)
Published Print	28 years, 7 months ago (Jan. 21, 1997)

Funders 0

None

BibTeX

@article{Zhang_1997, title={Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.2.569}, DOI={10.1073/pnas.94.2.569}, number={2}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Zhang, Dong-Er and Zhang, Pu and Wang, Nai-dy and Hetherington, Christopher J. and Darlington, Gretchen J. and Tenen, Daniel G.}, year={1997}, month=jan, pages={569–574} }

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