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

Abstract

The zinc-finger transcription factor GATA-2 plays a critical role in maintaining the pool of early hematopoietic cells. To define its specific functions in the proliferation, survival, and differentiation of hematopoietic cells, we analyzed the hematopoietic potential of GATA-2−/− cells in in vitro culture systems for proliferation and maintenance of uncommitted progenitors or differentiation of specific lineages. From a two-step in vitro differentiation assay of embryonic stem cells and in vitro culture of yolk sac cells, we demonstrate that GATA-2 is required for the expansion of multipotential hematopoietic progenitors and the formation of mast cells, but dispensable for the terminal differentiation of erythroid cells and macrophages. The rare GATA-2−/− multipotential progenitors that survive proliferate poorly and generate small colonies with extensive cell death, implying that GATA-2 may play a role in both the proliferation and survival of early hematopoietic cells. To explore possible mechanisms resulting in the hematopoietic defects of GATA-2−/− cells, we interbred mutant mouse strains to assess the effects of p53 loss on the behavior of GATA-2−/− hematopoietic cells. Analysis of GATA-2−/−/p53−/− compound-mutant embryos shows that the absence of p53 partially restores the number of total GATA-2−/− hematopoietic cells, and therefore suggests a potential link between GATA-2 and p53 pathways.