HIF-2α regulates murine hematopoietic development in an erythropoietin-dependent manner

Marzia Scortegagna, Kan Ding, Quiyang Zhang, Yavuz Oktay, Michael J. Bennett, Michael Bennett, John M. Shelton, James A. Richardson, Orson Moe, Joseph A. Garcia

Research output: Contribution to journalArticlepeer-review

186 Scopus citations


Erythropoiesis in the adult mammal depends critically on erythropoietin, an inducible cytokine with pluripotent effects. Erythropoietin gene expression increases under conditions associated with lowered oxygen content such as anemia and hypoxia. HIF-1α, the founding member of the hypoxia-inducible factor (HIF) alpha class, was identified by its ability to bind and activate the hypoxia-responsive enhancer in the erythropoietin regulatory region in vitro. The existence of multiple HIF alpha members raises the question of which HIF alpha member or members regulates erythropoietin expression in vivo. We previously reported that mice lacking wild-type HIF-2α, encoded by the EPAS1 gene, exhibit pancytopenia. In this study, we have characterized the etiology of this hematopoietic phenotype. Molecular studies of EPAS1-null kidneys reveal dramatically decreased erythropoietin gene expression. EPAS1-null as well as heterozygous mice have impaired renal erythropoietin induction in response to hypoxia. Treatment of EPAS1-null mice with exogenous erythropoietin reverses the hematopoietic and other defects. We propose that HIF-2α is an essential regulator of murine erythropoietin production. Impairments in HIF signaling, involving either HIF-1α or HIF-2α, may play a prominent role in conditions involving altered hematopoietic or erythropoietin homeostasis.

Original languageEnglish (US)
Pages (from-to)3133-3140
Number of pages8
Issue number8
StatePublished - Apr 15 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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