Blood Journal
Leading the way in experimental and clinical research in hematology

Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia

  1. Ellen van Rooijen1,2,
  2. Emile E. Voest1,
  3. Ive Logister1,2,
  4. Jeroen Korving2,
  5. Thorsten Schwerte3,
  6. Stefan Schulte-Merker2,
  7. Rachel H. Giles1,*, and
  8. Fredericus J. van Eeden2,*
  1. 1Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands;
  2. 2Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center, Utrecht, The Netherlands; and
  3. 3Institute of Zoology, University of Innsbruck, Innsbruck, Austria


We have generated 2 zebrafish lines carrying inactivating germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene ortholog vhl. Mutant embryos display a general systemic hypoxic response, including the up-regulation of hypoxia-induced genes by 1 day after fertilization and a severe hyperventilation and cardiophysiologic response. The vhl mutants develop polycythemia with concomitantly increased epo/epor mRNA levels and erythropoietin signaling. In situ hybridizations reveal global up-regulation of both red and white hematopoietic lineages. Hematopoietic tissues are highly proliferative, with enlarged populations of c-myb+ hematopoietic stem cells and circulating erythroid precursors. Chemical activation of hypoxia-inducible factor signaling recapitulated aspects of the vhl−/− phenotype. Furthermore, microarray expression analysis confirms the hypoxic response and hematopoietic phenotype observed in vhl−/− embryos. We conclude that VHL participates in regulating hematopoiesis and erythroid differentiation. Injections with human VHLp30 and R200W mutant mRNA demonstrate functional conservation of VHL between mammals and zebrafish at the amino acid level, indicating that vhl mutants are a powerful new tool to study genotype-phenotype correlations in human disease. Zebrafish vhl mutants are the first congenital embryonic viable systemic vertebrate animal model for VHL, representing the most accurate model for VHL-associated polycythemia to date. They will contribute to our understanding of hypoxic signaling, hematopoiesis, and VHL-associated disease progression.

  • Submitted July 18, 2008.
  • Accepted February 24, 2009.
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