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J. Biol. Chem., Vol. 281, Issue 35, 25703-25711, September 1, 2006

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Hypoxia-inducible Factor-1 Deficiency Results in Dysregulated Erythropoiesis Signaling and Iron Homeostasis in Mouse Development^*

Donghoon Yoon, Yves D. Pastore¹, Vladimir Divoky^¶1, Enli Liu^||, Agnieszka E. Mlodnicka^**, Karin Rainey, Premysl Ponka, Gregg L. Semenza, Armin Schumacher^**, and Josef T. Prchal²

From the Hematology Section, University of Utah, Salt Lake City, Utah 84132, Centre Hospitalier Universitaire Vaudois, Lausanne 1005, Switzerland, ^¶Biology and Hemato/Oncology, Palacky University, Faculty of Medicine, Olomouc 772 00, Czech Republic, ^||Center for Cell and Gene Therapy and ^**Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 and Vascular Biology Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and McGill University, Montreal H3T 1E2, Quebec, Canada

Hypoxia-inducible factor-1 (HIF-1) regulates the transcription of genes whose products play critical roles in energy metabolism, erythropoiesis, angiogenesis, and cell survival. Limited information is available concerning its function in mammalian hematopoiesis. Previous studies have demonstrated that homozygosity for a targeted null mutation in the Hif1 gene, which encodes the hypoxia-responsive subunit of HIF-1, causes cardiac, vascular, and neural malformations resulting in lethality by embryonic day 10.5 (E10.5). This study revealed reduced myeloid multilineage and committed erythroid progenitors in HIF-1-deficient embryos, as well as decreased hemoglobin content in erythroid colonies from HIF-1-deficient yolk sacs at E9.5. Dysregulation of erythropoietin (Epo) signaling was evident from a significant decrease in mRNA levels of Epo receptor (EpoR) in Hif1^-/- yolk sac as well as Epo and EpoR mRNA in Hif1^-/- embryos. The erythropoietic defects in HIF-1-deficient erythroid colonies could not be corrected by cytokines, such as vascular endothelial growth factor and Epo, but were ameliorated by Fe-SIH, a compound delivering iron into cells independently of iron transport proteins. Consistent with profound defects in iron homeostasis, Hif1^-/- yolk sac and/or embryos demonstrated aberrant mRNA levels of hepcidin, Fpn1, Irp1, and frascati. We conclude that dysregulated expression of genes encoding Epo, EpoR, and iron regulatory proteins contributes to defective erythropoiesis in Hif1^-/- yolk sacs. These results identify a novel role for HIF-1 in the regulation of iron homeostasis and reveal unexpected regulatory differences in Epo/EpoR signaling in yolk sac and embryonic erythropoiesis.

Received for publication, March 13, 2006 , and in revised form, June 19, 2006.

^* This work was supported by National Institutes of Health Grant R01HL50077-11 (to J. T. P.), the Ministry of Education of the Czech Republic Grants MSM 0021620806 and MSM 6198959205, and National Institutes of Health Grant R01-HL55338 (to G. L. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Hematology Section, University of Utah, 30 North 1900 East, 4C416 SOM, Salt Lake City, UT 84132. Tel.: 801-585-3229; Fax: 801-585-3432; E-mail: Josef.Prchal{at}hsc.utah.edu.

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