Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis

Abstract

The zinc finger transcription factor GATA-2 plays a fundamental role in generating hematopoietic stem-cells in mammalian development. Less well defined is whether GATA-2 participates in adult stem-cell regulation, an issue we addressed using GATA-2 heterozygote mice that express reduced levels of GATA-2 in hematopoietic cells. While GATA

Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling

“…In addition, we demonstrate that the Gata2 gene is directly activated by Notch/RBPJ but repressed by HES-1 specifically in the C-Kit + cell population of the emerging AGM clusters. Thus, in Hes-deficient mutants, Gata2 is up-regulated, and the number of hematopoietic cluster cells increased, but they only contained nonfunctional hematopoietic cells, in agreement with previous work demonstrating that Gata2 levels need to be tightly regulated to generate and maintain functional HSCs (Ling et al, 2004;Rodrigues et al, 2005). Our experiments show that limiting Notch activity in the absence of HES can decrease the levels of Gata2 and partially restore the hematopoietic production from AGM cells.…”

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

“…In concordance with previously reported findings of a reduction of HSCs in Gata2 haploinsufficient mice 19 , Gata2 deletion resulted in a loss of the immunophenotypic LSK population (Fig S2D). However, in Lin -cKit + progenitors we observed a significant reduction of p57 and Smad7 mRNA in the Gata2 -/-background compared to littermate controls.…”

“…This could be due to a converted HSC signature or more likely to the loss of the Gata2-deficient HSCs in line with observations in haploinsufficient Gata2 mice 19 and with Gata2-deficient human BM showing a complete absence of the primitive CD38 -cells within the CD34 + progenitor compartment [43][44][45] . Even though we were limited to study progenitor-enriched Gata2-deficient cells we found these cells to exhibit a strong reduction of colony-forming ability and to be desensitized to TGFβ-induced growth arrest.…”

“…However, even though p57 mRNA 4 levels were robustly upregulated following treatment of hematopoietic progenitor cells with recombinant human TGF-β1 (from now on referred to as TGFβ), the response was delayed and dependent on de novo protein synthesis, indicating that p57 is not an immediate effector molecule in the TGFβ response. Instead, we have identified the transcription factor (TF) Gata2, previously described as an important regulator of HSC function with similar functions as TGFβ and p57, 19,20 as a Smaddependent, direct target of TGFβ signaling in hematopoietic progenitor cells. Our results further reveal a transcriptional network involving Gata2, p57 and members of the TGFβ signaling pathway.…”

Capsaicin promotes the development of burst-forming nits-erythroid (BFU-E) from mouse bone marrow cells

“…GATA-2 is highly expressed in HSCs and declines with blood cell maturation, implying that it is a key factor in the maintenance of stem cell function, but not in provoking cell fate decisions in the HSCs. An experiment using haploinsufficiency of GATA-2 in mice indicated that the level of GATA-2 selectively affected GM colony formation (Rodrigues et al, 2005). Down regulation of GATA-2 expression was required for stem cells to contribute to normal hematopoiesis in vivo.…”