Distinct C/EBP functions are required for eosinophil lineage commitment and maturation.
Hematopoietic differentiation involves the commitment of multipotent progenitors to a given lineage, followed by the maturation of the committed cells. To study the transcriptional events controlling these processes, we have investigated the role of C/EBP proteins in lineage choice of multipotent hematopoietic progenitors (MEPs) transformed by the E26 virus. We found that forced expression of either the alpha or beta isoforms of C/EBP in MEPs induced eosinophil differentiation and that in addition, C/EBPbeta could induce myeloid differentiation. Conversely, dominant-negative versions of C/EBPbeta inhibited myeloid differentiation. C/EBP-induced eosinophil differentiation could be separated into two distinct events, lineage commitment and maturation. Thus, eosinophils induced by transactivation-deficient C/EBPbeta alleles were found to be blocked in their maturation, whereas those expressing wild-type C/EBP proteins were not. Likewise, a 1-day activation of a conditional C/EBPbeta allele in multipotent progenitors led to the formation of immature eosinophils, whereas sustained activation produced mature eosinophils. These results show that C/EBP can induce both myeloid and eosinophil lineage commitment and that transactivation independent and dependent C/EBP functions are required during eosinophil lineage commitment and maturation, respectively.
European Molecular Biology Laboratory (EMBL), D69117, Heidelberg, Germany.
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C
Nerlov
K M
KM
McNagny
G
G
Döderlein
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E
Kowenz-Leutz
T
T
Graf
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002645:Chickens; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004804:Eosinophils / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins