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Molecular and Cellular Biology, December 2005, p. 10479-10491, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10479-10491.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factors 1{alpha} and 2{alpha} Regulate Trophoblast Differentiation

Karen D. Cowden Dahl,1,{dagger} Benjamin H. Fryer,1 Fiona A. Mack,1 Veerle Compernolle,2 Emin Maltepe,3 David M. Adelman,1,{ddagger} Peter Carmeliet,2 and M. Celeste Simon1,4*

The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium,2 University of California, San Francisco, San Francisco, California,3 Abramson Family Cancer Research Institute,1 Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191044

Received 8 June 2005/ Returned for modification 29 August 2005/ Accepted 15 September 2005

Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1{alpha} and HIF2{alpha}, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIF{alpha} and HIFß (ARNT) subunits. Placentas from Arnt–/– and Hif1{alpha}–/– Hif2{alpha}–/– embryos exhibit defective placental vascularization and aberrant cell fate adoption. HIF regulation of Mash2 promotes spongiotrophoblast differentiation, a prerequisite for trophoblast giant cell differentiation. In the absence of Arnt or Hif{alpha}, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, and cell fate decisions, demonstrating that O2 tension is a critical regulator of trophoblast lineage determination. This novel genetic approach provides new insights into the role of O2 tension in the development of life-threatening pregnancy-related diseases such as preeclampsia.

* Corresponding author. Mailing address: BRBII/III, Room 456, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5532. Fax: (215) 746-5511. E-mail: celeste2{at}mail.med.upenn.edu.

{dagger} Present address: College of Pharmacy, University of New Mexico, Albuquerque, NM 87131.

{ddagger} Present address: Department of General Surgery, NYU Medical Center, New York, NY 10016.

Molecular and Cellular Biology, December 2005, p. 10479-10491, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10479-10491.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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