Placental but Not Heart Defects Are Associated with Elevated Hypoxia-Inducible Factor α Levels in Mice Lacking Prolyl Hydroxylase Domain Protein 2
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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.
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Inducible, global deletion of PHD2 in adult mice resulted in severe erythrocytosis from a dramatic increase in renal EPO production (Hct values > 80%), as well as other organ pathologies, particularly when PHD3 was inactivated simultaneously.
“Inducible, global deletion of PHD2 in adult mice resulted in severe erythrocytosis from a dramatic increase in renal EPO production (Hct values > 80%), as well as other organ pathologies, in particular when PHD3 was inactivated simultaneously.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [238]
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References 39 · Cited by 401
- Authors
- Takeda, K., Ho, V. C., Takeda, H., Duan, L.-J., Nagy, A., & Fong, G.-H.
- Affiliations
- UConn Health (US)
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5
- Corresponding author
- Fong, Guo-Hua
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-11-01
- Volume
- 26
- Issue
- 22
- Pages
- 8336-8346
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1636770
- OpenAlex
- W2130456602
- Cited by
- 401
- References
- 39
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 14 · 2023: 11 · 2022: 20 · 2021: 18 · 2020: 23 · 2019: 14 · 2018: 10 · 2017: 11 · 2016: 31 · 2015: 29 · 2014: 21 · 2013: 29 · 2012: 17
- FWCI
- 33.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Uehara Memorial Foundation
- Shahed University
- National Heart, Lung, and Blood Institute (5P01HL70694, P01HL070694)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- PHD2, hypoxia-inducible factor alpha, placental development, heart development, embryonic lethality, trophoblast giant cells, spongiotrophoblast, TFEB, GCM1, myocardial development, interventricular septum, mouse embryo development
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Cardiovascular System, Heart Defects, Congenital, Mice, Inbred C57BL, Placenta, Procollagen-Proline Dioxygenase, Cell Hypoxia, Giant Cells, Mice, Knockout, Gene Targeting, Protein Isoforms, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1
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