Consequences of GATA-1 Deficiency in Megakaryocytes and Platelets
Consequences of GATA-1 Deficiency in Megakaryocytes and Platelets
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DOI：
10.1182/blood.v93.9.2867.409k24_2867_2875
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发表时间：
1999-05
期刊：
影响因子：
20.3
通讯作者：
P. Vyas;K. Ault;C. Jackson;S. Orkin;R. Shivdasani
中科院分区：
文献类型：
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作者：
P. Vyas;K. Ault;C. Jackson;S. Orkin;R. Shivdasani
在缺乏造血转录因子GATA-1的情况下，小鼠出现血小板减少症和巨核细胞数量增加，其特征是明显的超微结构异常。这些观察结果确定了GATA-1在巨核细胞形成中的关键作用，并提出了GATA-1如何影响巨核细胞成熟和血小板产生的问题。为了开始解决这个问题，我们对该谱系中缺乏GATA-1的小鼠产生的巨核细胞和血小板进行了更详细的检查。我们的分析表明，与正常巨核细胞相比，缺乏gata -1的原代巨核细胞在液体培养中表现出明显的过度增殖，这表明动物的巨核细胞增多症是无反应性的。在形态学上，这些突变的巨核细胞很小，并且显示出核和细胞质发育迟缓的证据。这些细胞中有很大一部分不发生内膜分裂，并且所有巨核细胞相关基因的mRNA表达水平明显较低，包括GPIbalpha、GPIbbeta、血小板因子4 （PF4）、c-mpl和p45 NF-E2。这些结果与GATA-1对巨核细胞分化程序的调控一致。突变动物的出血时间明显延长。gata -1缺陷的血小板表现出异常的超微结构，使人联想到它们起源于巨核细胞，并且在凝血酶或二磷酸腺苷（ADP）和肾上腺素的联合作用下，血小板激活表现出适度但选择性的缺陷。我们的研究结果表明，GATA-1在巨核细胞发育中具有多种功能，影响细胞的生长和成熟。
In the absence of the hematopoietic transcription factor GATA-1, mice develop thrombocytopenia and an increased number of megakaryocytes characterized by marked ultrastructural abnormalities. These observations establish a critical role for GATA-1 in megakaryopoiesis and raise the question as to how GATA-1 influences megakaryocyte maturation and platelet production. To begin to address this, we have performed a more detailed examination of the megakaryocytes and platelets produced in mice that lack GATA-1 in this lineage. Our analysis demonstrates that compared with their normal counterparts, GATA-1-deficient primary megakaryocytes exhibit significant hyperproliferation in liquid culture, suggesting that the megakaryocytosis seen in animals is nonreactive. Morphologically, these mutant megakaryocytes are small and show evidence of retarded nuclear and cytoplasmic development. A significant proportion of these cells do not undergo endomitosis and express markedly lower levels of mRNA of all megakaryocyte-associated genes tested, including GPIbalpha, GPIbbeta, platelet factor 4 (PF4), c-mpl, and p45 NF-E2. These results are consistent with regulation of a program of megakaryocytic differentiation by GATA-1. Bleeding times are significantly prolonged in mutant animals. GATA-1-deficient platelets show abnormal ultrastructure, reminiscent of the megakaryocytes from which they are derived, and exhibit modest but selective defects in platelet activation in response to thrombin or to the combination of adenosine diphosphate (ADP) and epinephrine. Our findings indicate that GATA-1 serves multiple functions in megakaryocyte development, influencing both cellular growth and maturation.