Role of GATA-1 in Proliferation and Differentiation of Definitive Erythroid and Megakaryocytic Cells In Vivo

Abstract

To elucidate the contributions of GATA-1 to definitive hematopoiesis in vivo, we have examined adult mice that were rendered genetically defective in GATA-1 synthesis (Takahashi et al, J Biol Chem272:12611, 1997). Because the GATA-1 gene is located on the X chromosome, which is randomly inactivated in every cell, heterozygous females can bear either an active wild-type or mutant (referred to asGATA-1.05) GATA-1 allele, consequently leading to variable anemic severity. These heterozygous mutant mice usually developed normally, but they began to die after 5 months. These affected animals displayed marked splenomegaly, anemia, and thrombocytopenia. Proerythroblasts and megakaryocytes massively accumulated in the spleens of the heterozygotes, and we showed that the neomycin resistance gene (which is the positive selection marker in ES cells) was expressed profusely in the abnormally abundant cells generated in the GATA-1.05 mutant females. We also observed hematopoiesis outside of the bone marrow in the affected mutant mice. These data suggest that a small number of GATA-1.05 mutant hematopoietic progenitor cells begin to proliferate vigorously during early adulthood, but because the cells are unable to terminally differentiate, this leads to progenitor proliferation in the spleen and consequently death. Thus, GATA-1 plays important in vivo roles for directing definitive hematopoietic progenitors to differentiate along both the erythroid and megakaryocytic pathways. The GATA-1 heterozygous mutant mouse shows a phenotype that is analogous to human myelodysplastic syndrome and thus may serve as a useful model for this disorder.

Antioxidant N‐acetyl‐l‐cysteine inhibits erythropoietin‐induced differentiation of erythroid progenitors derived from mouse fetal liver

“…NAC inhibited the induction of genes encoding transcription factors such as GATA1 and NF-E2 in response to Epo, which is consistent with previous observations in butyrateinduced K562 cells (Chenais et al, 2000). Because GATA1 and NF-E2 are essential for erythroid differentiation (Francastel et al, 1997;Igarashi et al, 1995;Pevny et al, 1991;Suwabe et al, 1998;Takahashi et al, 1998), ROS might induce differentiation via these transcription factors.…”

“…1B) and coproporphyrinogen oxidase (data not shown). Gene expression of the transcription factors NF-E2 (composed of MafK and p45), EKLF, and GATA1, which are critical for b major -globin gene transcription and erythroid differentiation (Francastel et al, 1997;Igarashi et al, 1995;Nuez et al, 1995;Pevny et al, 1991;Suwabe et al, 1998;Takahashi et al, 1998), was also upregulated (Fig. 1CeF).…”

Three parameters, plasma thrombopoietin levels, plasma glycocalicin levels and megakaryocyte culture, distinguish between different causes of congenital thrombocytopenia

“…To date, not much is known about the factors involved in the final stages of megakaryocyte maturation and proplatelet formation. Two transcription factor knock-out mice, NF-E2 and GATA-1, have been described that were both severely thrombocytopenic (Shivdasani et al, 1995(Shivdasani et al, , 1997Lecine et al, 1998;Takahashi et al, 1998). NF-E2 knock-out mice have normal Tpo levels and normal numbers of…”

Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N‐terminal domain

“…However, we have found that the Gata1 G1.05/X mice suffer from erythroid leukemias (Shimizu et al 2008). Although the Gata1 G1.05/X mice survive to adulthood, some of them present splenomegaly, anemia and thrombocytopenia that are indicative of leukemia (Takahashi et al 1998). We subsequently found that majority of the Gata1 G1.05/X mice suffer from erythroleukemia by 200 days after birth (Shimizu et al 2004a).…”

“…Due to random inactivation of the X-chromosome, heterozygous female (Gata1 G1.05/X ) mice harbor two types of hematopoietic progenitor cells: one is harboring active Gata1 and inactive Gata1 knockdown (G1.05) alleles, whereas the other harbors inactive Gata1 but active G1.05 alleles (Takahashi et al 1998). As the former progenitors produce hematopoietic cells enough to sustain mouse development, we have maintained the Gata1 knockdown allele through female Gata1 G1.05/X mice.…”