FEF-2α regulates murine hematopoietic development in an erythropoietin-dependent manner
FEF-2α regulates murine hematopoietic development in an erythropoietin-dependent manner
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DOI：
10.1182/blood-2004-05-1695
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发表时间：
2005-04-15
期刊：
影响因子：
20.3
通讯作者：
Garcia, JA
中科院分区：
文献类型：
--
作者：
Scortegagna, M;Ding, K;Garcia, JA
成年哺乳动物的红细胞生成在很大程度上依赖于促红细胞生成素，这是一种具有多潜能作用的可诱导细胞因子。促红细胞生成素基因在贫血和缺氧等含氧量较低的条件下表达增加。HIF-1α是低氧诱导因子(HIF)α类的创始成员，它在体外结合和激活促红细胞生成素调节区的低氧反应增强子的能力被鉴定。多个HIFα成员的存在引发了一个或多个HIFα成员在体内调节促红细胞生成素表达的问题。我们之前曾报道，缺乏由EPAS1基因编码的野生型HIF-2α的小鼠表现出全血细胞减少症。在这项研究中，我们描述了这种造血表型的病因学特征。EPAS1缺失肾脏的分子研究显示促红细胞生成素基因表达显著降低。EPAS1缺失和杂合子小鼠对低氧的反应损害了肾脏促红细胞生成素的诱导。用外源性促红细胞生成素治疗EPAS1基因缺失的小鼠可以逆转血细胞和其他缺陷。我们认为HIF-2α是小鼠红细胞生成素的重要调节因子。HIF信号的损伤，包括HIF-1α或HIF-2α，可能在涉及血液平衡或促红细胞生成素动态平衡改变的情况下发挥显著作用。(C)2005年，由美国血液病学会提供。
Erythropoiesis in the adult mammal depends critically on erythropoietin, an inducible cytokine with pluripotent effects. Erythropoietin gene expression increases under conditions associated with lowered oxygen content such as anemia and hypoxia. HIF-1 alpha, the founding member of the hypoxia-inducible factor (HIF) alpha class, was identified by its ability to bind and activate the hypoxia-responsive enhancer in the erythropoietin regulatory region in vitro. The existence of multiple HIF alpha members raises the question of which HIF alpha member or members regulates erythropoietin expression in vivo. We previously reported that mice lacking wild-type HIF-2 alpha, encoded by the EPAS1 gene, exhibit pancytopenia. In this study, we have characterized the etiology of this hematopoietic phenotype. Molecular studies of EPAS1-null kidneys reveal dramatically decreased erythropoietin gene expression. EPAS1-null as well as heterozygous mice have impaired renal erythropoietin induction in response to hypoxia. Treatment of EPAS1-null mice with exogenous erythropoietin reverses the hematopoletic and other defects. We propose that HIF-2 alpha is an essential regulator of murine erythropoletin production. Impairments in HIF signaling, involving either HIF-1 alpha or HIF-2 alpha, may play a prominent role in conditions involving altered hematopoletic or erythropoietin homeostasis. (c) 2005 by The American Society of Hematology.