Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropolesis
Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropolesis
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DOI：
10.1182/blood-2007-09-115121
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发表时间：
2008-04-15
期刊：
影响因子：
20.3
通讯作者：
Ohneda, Kinuko
中科院分区：
文献类型：
--
作者：
Gutierrez, Laura;Tsukamoto, Saho;Ohneda, Kinuko
转录因子GATA1在多种造血系中表达，在胚胎阶段的正常造血发育中发挥重要作用。GATA1缺失型胚胎的致命性使人们无法确定其在成人红细胞生成中的作用。在这里，我们使用表达干扰素或他莫昔芬诱导的Cre重组酶(分别为Mx-Cre和Tx-Cre)的条件性GATA1基因敲除小鼠，研究了GATA1缺失对成年红细胞生成的影响。MX-Cre介导的GATA1重组虽然不完全，但导致GATA1缺失的红系细胞在前红细胞阶段成熟停滞，血小板减少，并导致脾中巨核细胞过度增殖。Tx-Cre介导的GATA1重组导致骨髓和脾中红细胞室的耗尽。在缺乏GATA1的情况下，骨髓中早期和晚期红系祖细胞的形成显著减少。此外，在溶血剂的治疗下，这些小鼠未能激活应激性红细胞生成反应，尽管促红细胞生成素水平上升。这些结果表明，除了成人巨核细胞生成所需的GATA1外，GATA1对于稳定状态的红细胞生成和贫血后的红细胞扩增也是必需的。因此，在成年小鼠身上切除GATA1会导致类似于人类再生障碍性疾病的情况。
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-Cre-mediated 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 erythrold expansion in response to anemia. Thus, ablation of Gata1 in adult mice results in a condition resembling aplastic crisis in human.