von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesis
Michele M. Hickey, … , W. Kimryn Rathmell, M. Celeste Simon
Michele M. Hickey, … , W. Kimryn Rathmell, M. Celeste Simon
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3879-3889. https://doi.org/10.1172/JCI32614.
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Research Article Hematology

von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesis

Abstract

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–1α (HIF-1α) 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 (VhlR/R). VhlR/R mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2α isoform, was upregulated in ES cells and tissues from VhlR/R mice. Furthermore, we observed a striking phenotype in VhlR/R spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of VhlR/R splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2α genes promotes splenic erythropoiesis, resulting in the development of polycythemia in VhlR/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.

Authors

Michele M. Hickey, Jennifer C. Lam, Natalie A. Bezman, W. Kimryn Rathmell, M. Celeste Simon

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Figure 4

HIF target gene expression is increased in VhlR/R mice.

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HIF target gene expression is increased in VhlR/R mice. ...
(A and B) Serum levels of VEGF and Epo were determined by ELISA; pooled results from mice of varying ages are shown. (A) VEGF levels were 1.3-fold greater in VhlR/R mice than in WT and VhlR/+ mice. *P < 0.002. (B) Epo levels were 1.8-fold greater in VhlR/R mice (P < 0.08). (C–F) TaqMan real-time PCR analysis of HIF gene expression in kidney (C and D), liver (E), and spleen (F). The expression of several genes, most notably HIF-2α–preferential targets such as Glut-1, PAI-1, and VEGF, was increased in tissues isolated from VhlR/R mice compared with those of WT mice. *P < 0.05; **P < 0.007; #P < 0.059 (trending toward significance). Renal Epo mRNA expression was increased 1.3-fold (P < 0.09) in VhlR/R mice with increased serum Epo levels (D).