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Blood, 18 June 2009, Vol. 113, No. 25, pp. 6449-6460. Prepublished online as a Blood First Edition Paper on March 20, 2009; DOI 10.1182/blood-2008-07-167890. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2008-07-167890v1 113/25/6449    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by van Rooijen, E. Articles by van Eeden, F. J. PubMed PubMed Citation Articles by van Rooijen, E. Articles by van Eeden, F. J. Related Collections Hematopoiesis and Stem Cells Red Cells, Iron, and Erythropoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia Ellen van Rooijen1,2, Emile E. Voest1, Ive Logister1,2, Jeroen Korving2, Thorsten Schwerte3, Stefan Schulte-Merker2, Rachel H. Giles1,*, and Fredericus J. van Eeden2,* 1 Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands; 2 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center, Utrecht, The Netherlands; and 3 Institute 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Dissecting VHL-associated pathologies Eric Metzen and Ulf Brockmeier Blood 2009 113: 6273-6274. [Abstract] [Full Text] [PDF] This article has been cited by other articles: A Model for Chuvash Polycythemia Journal Watch Oncology and Hematology, July 28, 2009; 2009(728): 2 - 2. [Full Text] E. Metzen and U. Brockmeier Dissecting VHL-associated pathologies Blood, June 18, 2009; 113(25): 6273 - 6274. [Abstract] [Full Text] [PDF]

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