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Acute postnatal ablation of Hif-2alpha results in anemia.

Adaptive transcriptional responses to oxygen deprivation (hypoxia) are mediated by the hypoxia-inducible factors (HIFs), heterodimeric transcription factors composed of two basic helix-loop-helix-PAS family proteins. The transcriptional activity of HIF is determined by the hypoxic stabilization of the HIF-alpha proteins. HIF-1alpha and HIF-2alpha exhibit high sequence homology but have different mRNA expression patterns; HIF-1alpha is expressed ubiquitously whereas HIF-2alpha expression is more restricted to certain tissues, e.g., the endothelium, lung, brain, and neural crest derivatives. Germ-line deletion of either HIF subunit is embryonic lethal with unique features suggesting important roles for both HIF-alpha isoforms. Global deletion of Hif-2alpha results in distinct phenotypes depending on the mouse strain used for the mutation, clearly demonstrating an important role for HIF-2alpha in mouse development. The function of HIF-2alpha in adult life, however, remains incompletely understood. In this study, we describe the generation of a conditional murine Hif-2alpha allele and the effect of its acute postnatal ablation. Under very stringent conditions, we ablate Hif-2alpha after birth and compare the effect of acute global deletion of Hif-2alpha and Hif-1alpha. Our results demonstrate that HIF-2alpha plays a critical role in adult erythropoiesis, with acute deletion leading to anemia. Furthermore, although HIF-1alpha was first purified and cloned based on its affinity for the human erythropoietin (EPO) 3' enhancer hypoxia response element (HRE) and regulates Epo expression during mouse embryogenesis, HIF-2alpha is the critical alpha isoform regulating Epo under physiologic and stress conditions in adults.

Pubmed ID: 17284606

Authors

  • Gruber M
  • Hu CJ
  • Johnson RS
  • Brown EJ
  • Keith B
  • Simon MC

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 13, 2007

Associated Grants

  • Agency: PHS HHS, Id: 66310

Mesh Terms

  • Anemia
  • Animals
  • Anoxia
  • Basic Helix-Loop-Helix Transcription Factors
  • Erythropoiesis
  • Erythropoietin
  • Gene Expression Regulation
  • Mice
  • Mice, Knockout
  • Phenotype
  • Protein Isoforms
  • Response Elements
  • Stress, Physiological