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¹ Department of Cell Biology and Genetics, Erasmus University Medical Center, 3000 DR Rotterdam, Netherlands
² Department of Immunology, Erasmus University Medical Center, 3000 DR Rotterdam, Netherlands
³ Department of Hematology, Erasmus University Medical Center, 3000 DR Rotterdam, Netherlands
⁴ Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115

Address correspondence to Elaine Dzierzak, Eramus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, Netherlands. Phone: 31-10-408-7172; Fax: 31-10-408-9468; email: e.dzierzak{at}eramusmc.nl

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.

Key Words: GATA-2 • hematopoietic stem cells • AGM • haploinsufficiency • gene dosage

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