Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis

Abstract

The transcription factor Gata1 is expressed in several hematopoietic lineages and plays essential roles in normal hematopoietic development during embryonic stages. The lethality of Gata1-null embryos has precluded determination of its role in adult erythropoiesis. Here we have examined the effects of Gata1 loss in adult erythropoiesis using conditional Gata1 knockout mice expressing either interferon-or tamoxifen-inducible Cre recombinase (Mx-Cre and Tx-Cre, respectively). Mx-Cre-mediated Gata1 recombination, although incomplete, resulted in maturation arrest of Gata1-null erythroid cells at the proerythroblast stage, thrombocytopenia, and excessive proliferation of megakaryocytes in the spleen. Tx-Cremediated Gata1 recombination resulted in depletion of the erythroid compartment in bone marrow and spleen. Formation of the early and late erythroid progenitors in bone marrow was significantly reduced in the absence of Gata1. Furthermore, on treatment with a hemolytic agent, these mice failed to activate a stress erythropoietic response, despite the rising erythropoietin levels. These results indicate that, in addition to the requirement of Gata1 in adult megakaryopoiesis, Gata1 is necessary for steady-state erythropoiesis and for erythroid expansion in response to anemia. Thus, ablation of Gata1 in adult mice results in a condition resembling aplastic crisis in human. IntroductionProduction of mature blood cells from the pluripotent hematopoietic stem cells is continuous throughout life. This process is controlled by combinatorial functions of lineage-specific and ubiquitous transcription factors. The zinc finger transcription factor Gata1 is a prototype of lineage-specific transcription factors, with restricted expression in several myeloid lineages. 1,2 Gene ablation studies of Gata1 in mice revealed its essential role in erythroid cell development. Embryos lacking Gata1 die at approximately embryonic day 11.5 because of arrested maturation of primitive erythroid cells. 3 A similar phenotype was observed in embryos bearing a Gata1 knockdown mutation (Gata1.05) that causes 95% reduction of Gata1 mRNA level in erythroid cells. 4 A critical role for Gata1 in megakaryocyte maturation and platelet formation has been shown in mice with megakaryocyte-specific Gata1 deficiency. 5,6 A remarkable phenotype of these mutant mice is that defective maturation of megakaryocytes is associated with excessive proliferation, suggesting that Gata1 inhibits cell proliferation during megakaryocytic maturation.Although roles for Gata1 in postnatal megakaryopoiesis have been thoroughly investigated, the embryonic lethality caused by Gata1 deficiency in erythroid precursors has precluded studies of its role in postnatal erythropoiesis. In adults, the rate of red cell production in the steady-state condition is much lower than that in the fetal and neonatal stages. However, in response to erythropoietic stress, the rate of erythropoiesis is rapidly increased. 7 The plasma levels of erythropoietin (Epo), the central regulator of erythr...

Differential Contribution of the Gata1 Gene Hematopoietic Enhancer to Erythroid Differentiation

“…GATA1 is expressed in erythroid cells, megakaryocytes, mast cells, eosinophils, and dendritic cells (8,17,30,53) and in Sertoli cells in the testis (12,51). GATA1 has been shown to be essential for erythroid cell differentiation in vivo (6,9,40). Closer examination of Gata1-deficient mice and cells revealed that without GATA1, erythroid cells fail to mature beyond the proerythroblast stage (29,47).…”

Lineage-specific combinatorial action of enhancers regulates mouse erythroid Gata1 expression

“…7,9 Moreover, ablation of Gata1 expression in adult mice also results in anemia and severe thrombocytopenia from a similar block in erythroid and megakaryocyte maturation as that seen in developmental hematopoiesis. 10 Regulation of the level and spatiotemporal pattern of Gata1 transcription is critical during at least 2 key stages in hematopoiesis for orderly erythroid and megakaryocyte differentiation. In mouse, multipotential progenitor cells initiating Gata1 expression are committed to an erythroid/megakaryocyte (EM) fate.…”

Leukemogenesis in Down syndrome

“…These results unequivocally indicate that GATA1 is required for erythroid commitment and erythropoiesis in the early stage of hematopoiesis. In addition, well-lobulated mature megakaryocytes that are positive for acetylcholine esterase (AchE) staining are accumulated in the hematopoietic organs of conditional Gata1-null mice, indicating that GATA1 is dispensable from the early stage of megakaryopoiesis and megakaryocyte development to matured polyploid megakaryocytes [56].…”

“…Adult Gata1-null mice produced by a conditional deletion of whole coding exons suffer from severe anemia and thrombocytopenia [56]. These mice lack erythroid progenitors, showing a phenotype resembling that of pure red cell aplasia.…”