GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.
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.
Department of Cell Biology and Genetics, Eramus University Medical Center, 3000 DR Rotterdam, Netherlands.
Kam-Wing
KW
Ling
Katrin
K
Ottersbach
Jan Piet
JP
van Hamburg
Aneta
A
Oziemlak
Fong-Ying
FY
Tsai
Stuart H
SH
Orkin
Rob
R
Ploemacher
Rudi W
RW
Hendriks
Elaine
E
Dzierzak
D000818:Animals; D001011:Aorta / Q000502:physiology; D001853:Bone Marrow / Q000502:physiology; D002588:Cesium Radioisotopes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D050989:GATA2 Transcription Factor; D018628:Gene Dosage; D006066:Gonads / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007150:Immunohistochemistry; D008650:Mesonephros / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000033:anatomy & histology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D002588:Cesium Radioisotopes; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D014157:Transcription Factors