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PMID: 15466621 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.

The Journal of experimental medicine ·Vol. 200 ·No. 7 ·2004-10-04 ·Pages 871-82

Ling KW, Ottersbach K, van Hamburg JP, Oziemlak A, Tsai FY, Orkin SH, Ploemacher R, Hendriks RW, Dzierzak E

Abstract

GATA-2 is an essential transcription factor in the hematopoietic system that is expressed in hematopoietic stem cells (HSCs) and progenitors. Complete deficiency of GATA-2 in the mouse leads to severe anemia and embryonic lethality. The role of GATA-2 and dosage effects of this transcription factor in HSC development within the embryo and adult are largely unexplored. Here we examined the effects of GATA-2 gene dosage on the generation and expansion of HSCs in several hematopoietic sites throughout mouse development. We show that a haploid dose of GATA-2 severely reduces production and expansion of HSCs specifically in the aorta-gonad-mesonephros region (which autonomously generates the first HSCs), whereas quantitative reduction of HSCs is minimal or unchanged in yolk sac, fetal liver, and adult bone marrow. However, HSCs in all these ontogenically distinct anatomical sites are qualitatively defective in serial or competitive transplantation assays. Also, cytotoxic drug-induced regeneration studies show a clear GATA-2 dose-related proliferation defect in adult bone marrow. Thus, GATA-2 plays at least two functionally distinct roles during ontogeny of HSCs: the production and expansion of HSCs in the aorta-gonad-mesonephros and the proliferation of HSCs in the adult bone marrow.

MeSH Terms
Animals Aorta/physiology Bone Marrow/physiology Cesium Radioisotopes DNA-Binding Proteins/genetics,physiology Female Flow Cytometry GATA2 Transcription Factor Gene Dosage Gonads/physiology Hematopoietic Stem Cells/physiology Immunohistochemistry Mesonephros/physiology Mice Mice, Inbred C57BL Microscopy, Confocal Polymerase Chain Reaction/methods Spleen/anatomy & histology Time Factors Transcription Factors/genetics,physiology
Chemicals
Cesium Radioisotopes DNA-Binding Proteins GATA2 Transcription Factor Gata2 protein, mouse Transcription Factors
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Ling Kam-Wing
Department of Cell Biology and Genetics, Eramus University Medical Center, 3000 DR Rotterdam, Netherlands.
Ottersbach Katrin
van Hamburg Jan Piet
Oziemlak Aneta
Tsai Fong-Ying
Orkin Stuart H
Ploemacher Rob
Hendriks Rudi W
Dzierzak Elaine
References (37)
37 references, click to expand
  1. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo.
    EMBO J. 2000 Jun 1;19(11):2465-74 PMID: 10835345
  2. Pluripotent hematopoietic stem cells contain high levels of mRNA for c-kit, GATA-2, p45 NF-E2, and c-myb and low levels or no mRNA for c-fms and the receptors for granulocyte colony-stimulating factor and interleukins 5 and 7.
    Proc Natl Acad Sci U S A. 1995 May 9;92(10):4601-5 PMID: 7538677
  3. Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo.
    Immunity. 2000 Oct;13(4):423-31 PMID: 11070161
  4. Decreased expression of transcription factor GATA-2 in haematopoietic stem cells in patients with aplastic anaemia.
    Br J Haematol. 2001 Apr;113(1):52-7 PMID: 11328281
  5. Cloning of the Ly-6A (Sca-1) gene locus and identification of a 3' distal fragment responsible for high-level gamma-interferon-induced expression in vitro.
    Br J Haematol. 2001 Sep;114(3):724-30 PMID: 11553006
  6. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo.
    Immunity. 2002 May;16(5):661-72 PMID: 12049718
  7. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta.
    Immunity. 2002 May;16(5):673-83 PMID: 12049719
  8. Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors.
    EMBO J. 2002 Jun 17;21(12):3039-50 PMID: 12065417
  9. GATA-2 and GATA-2/ER display opposing activities in the development and differentiation of blood progenitors.
    EMBO J. 2002 Jun 17;21(12):3060-9 PMID: 12065419
  10. GATA factors are essential for transcription of the survival gene E4bp4 and the viability response of interleukin-3 in Ba/F3 hematopoietic cells.
    J Biol Chem. 2002 Jul 26;277(30):27144-53 PMID: 12023274
  11. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver.
    Development. 2002 Nov;129(21):4891-9 PMID: 12397098
  12. GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21(WAF1) and p27(Kip1) proteins.
    Blood. 2002 Nov 15;100(10):3512-20 PMID: 12393444
  13. Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A-null mice.
    Blood. 2003 Jan 15;101(2):517-23 PMID: 12393491
  14. Enhanced green fluorescent protein targeted to the Sca-1 (Ly-6A) locus in transgenic mice results in efficient marking of hematopoietic stem cells in vivo.
    Exp Hematol. 2003 Feb;31(2):159-67 PMID: 12591281
  15. Expression and domain-specific function of GATA-2 during differentiation of the hematopoietic precursor cells in midgestation mouse embryos.
    Blood. 2003 Aug 1;102(3):896-905 PMID: 12689939
  16. Studies of hematopoietic stem cells spared by 5-fluorouracil.
    J Exp Med. 1984 Mar 1;159(3):679-90 PMID: 6699542
  17. Life span of multipotential hematopoietic stem cells in vivo.
    J Exp Med. 1990 May 1;171(5):1407-18 PMID: 2159048
  18. Clonal and systemic analysis of long-term hematopoiesis in the mouse.
    Genes Dev. 1990 Feb;4(2):220-32 PMID: 1970972
  19. Mouse hematopoietic stem cells.
    Blood. 1991 Sep 15;78(6):1395-402 PMID: 1884012
  20. Clonal, in vivo behavior of the totipotent hematopoietic stem cell.
    Semin Immunol. 1991 Nov;3(6):349-55 PMID: 1686833
  21. Ectopic expression of a conditional GATA-2/estrogen receptor chimera arrests erythroid differentiation in a hormone-dependent manner.
    Genes Dev. 1993 Jun;7(6):1097-109 PMID: 8504932
  22. DNA-binding specificity of GATA family transcription factors.
    Mol Cell Biol. 1993 Jul;13(7):3999-4010 PMID: 8321207
  23. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.
    Cell. 1996 Jan 26;84(2):321-30 PMID: 8565077
  24. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9 PMID: 8622955
  25. Definitive hematopoiesis is autonomously initiated by the AGM region.
    Cell. 1996 Sep 20;86(6):897-906 PMID: 8808625
  26. Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12359-63 PMID: 8901586
  27. Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation.
    Blood. 1997 May 15;89(10):3636-43 PMID: 9160668
  28. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac.
    Immunity. 1997 Sep;7(3):335-44 PMID: 9324354
  29. Alternative promoters regulate transcription of the mouse GATA-2 gene.
    J Biol Chem. 1998 Feb 6;273(6):3625-34 PMID: 9452491
  30. Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis.
    Blood. 1999 Jan 15;93(2):488-99 PMID: 9885210
  31. The mouse GATA-2 gene is expressed in the para-aortic splanchnopleura and aorta-gonads and mesonephros region.
    Blood. 1999 Jun 15;93(12):4196-207 PMID: 10361117
  32. A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal.
    Genes Dev. 1999 Jul 15;13(14):1847-60 PMID: 10421636
  33. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
    Nat Genet. 1999 Oct;23(2):166-75 PMID: 10508512
  34. DNA-binding specificities of the GATA transcription factor family.
    Mol Cell Biol. 1993 Jul;13(7):4011-22 PMID: 8321208
  35. An early haematopoietic defect in mice lacking the transcription factor GATA-2.
    Nature. 1994 Sep 15;371(6494):221-6 PMID: 8078582
  36. Development of hematopoietic stem cell activity in the mouse embryo.
    Immunity. 1994 Jul;1(4):291-301 PMID: 7889417
  37. Overexpression of GATA-2 inhibits erythroid and promotes megakaryocyte differentiation.
    Exp Hematol. 2000 Dec;28(12):1423-31 PMID: 11146164
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20031556
Published
2004-10-04
Pages
871-82
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213282
Subset
IM
Grants
NIDDK NIH HHS · R01 DK51077 · United States
External Links
PubMed source DOI: 10.1084/jem.20031556 PMC Full Text View journal details
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