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Molecular and Cellular Biology, November 2006, p. 8336-8346, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00425-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Placental but Not Heart Defects Are Associated with Elevated Hypoxia-Inducible Factor {alpha} Levels in Mice Lacking Prolyl Hydroxylase Domain Protein 2{triangledown} ,{dagger}

Kotaro Takeda,1 Vivienne C. Ho,1 Hiromi Takeda,1 Li-Juan Duan,1 Andras Nagy,2 and Guo-Hua Fong1*

Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030,1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X52

Received 10 March 2006/ Returned for modification 21 April 2006/ Accepted 27 August 2006

PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor {alpha} subunits (HIF-{alpha}). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2–/– embryos died between embryonic days 12.5 and 14.5 whereas Phd1–/– or Phd3–/– mice were apparently normal. In Phd2–/– mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gcm1. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-{alpha} protein levels in the placenta and the embryo proper, there was no specific HIF-{alpha} increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.

* Corresponding author. Mailing address: Center for Vascular Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3501. Phone: (860) 679-2373. Fax: (860) 679-1201. E-mail: fong{at}nso2.uchc.edu.

{triangledown} Published ahead of print on 11 September 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 8336-8346, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00425-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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