ZFIN ID: ZDB-PUB-090324-15
Zebrafish mutants in the von Hippel-Lindau (VHL) tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia
van Rooijen, E., Voest, E.E., Logister, I., Korving, J., Schwerte, T., Schulte-Merker, S., Giles, R.H., and van Eeden, F.J.
Date: 2009
Source: Blood   113(25): 6449-6460 (Journal)
Registered Authors: Logister, Ive, Schulte-Merker, Stefan, Schwerte, Thorsten, van Eeden, Freek, van Rooijen, Ellen
Keywords: none
Microarrays: GEO:GSE14866
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Cell Lineage
  • Conserved Sequence
  • Disease Models, Animal*
  • Gene Knockout Techniques
  • Germ-Line Mutation
  • Hematopoiesis/genetics
  • Humans
  • Hypoxia/genetics*
  • Hypoxia/physiopathology
  • Molecular Sequence Data
  • Point Mutation
  • Polycythemia/genetics*
  • Polycythemia/physiopathology
  • RNA, Messenger/administration & dosage
  • RNA, Messenger/genetics
  • RNA, Messenger/pharmacology
  • Recombinant Fusion Proteins/physiology
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Synteny
  • Tumor Suppressor Proteins/deficiency
  • Tumor Suppressor Proteins/genetics
  • Tumor Suppressor Proteins/physiology*
  • Von Hippel-Lindau Tumor Suppressor Protein/chemistry
  • Von Hippel-Lindau Tumor Suppressor Protein/genetics
  • Von Hippel-Lindau Tumor Suppressor Protein/physiology
  • Zebrafish
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
PubMed: 19304954 Full text @ Blood
We have generated two 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 upregulation of hypoxia-induced genes by 1 day post-fertilization and a severe hyperventilation and cardiophysiological response. vhl mutants develop polycythemia with concomitantly increased epo/epor mRNA levels and Epo 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(+) HSCs and circulating erythroid precursors. Chemical activation of Hif-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.