Von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesis
Von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesis
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DOI：
10.1172/jci32614
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
--
作者：
Hickey, Michele M.;Lam, Jennifer C.;Simon, M. Celeste
von Hippel-Lindau（VHL）肿瘤抑制蛋白（pVHL）中的R200 W突变是独特的，因为它与肿瘤发展无关，而是与Chuvash红细胞增多症相关，Chuvash红细胞增多症是一种遗传性疾病，其特征在于红细胞压积升高和促红细胞生成素和VEGF血清水平升高。先前的研究已经暗示了这种疾病中的缺氧诱导因子-1 α（HIF-1 α）信号传导，尽管这种突变对pVHL功能的影响尚未完全了解。为了探索这种红细胞增多症的发病机制，我们产生了R200 W突变纯合子小鼠（Vbl（R/R））。Vbl（R/R）小鼠出现与人类疾病高度相似的红细胞增多症。HIF蛋白的活性，特别是HIF-2 α亚型，在Vbl（R/R）小鼠的ES细胞和组织中上调。此外，我们在Vbl（R/R）脾中观察到显著的表型，具有更多数量的红系祖细胞和巨核细胞，并且体外Vhl（R/R）脾细胞的红系分化增加。这些发现表明，关键HIF-2 α基因的表达增强促进了脾红细胞生成，导致Vbl（R/R）小鼠红细胞增多症的发展。该小鼠模型忠实地再现了这种VHL相关综合征，并且代表了研究红细胞增多症和研究潜在治疗方法的有用工具。
The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-l alpha (HIF-1 alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vbl(R/R)). Vbl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2 alpha isoform, was upregulated in ES cells and tissues from Vbl(R/R) mice. Furthermore, we observed a striking phenotype in Vbl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2 alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vbl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics.