Hypoxia-inducible factors 1α and 2α regulate trophoblast differentiation

Karen D. Cowden Dahl, Benjamin H. Fryer, Fiona A. Mack, Veerle Compernolle, Emin Maltepe, David M. Adelman, Peter Carmeliet, M. Celeste Simon

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), H/F1α and HIF2α, are essential for determining marine placental cell fates. HIF is a heterodimer composed of HIFα and HIFβ (ARNT) subunits. Placentas from Arnt-/- and Hif1α-/- Hif2α-/- 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 Hifα, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, aad 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.

Original languageEnglish (US)
Pages (from-to)10479-10491
Number of pages13
JournalMolecular and cellular biology
Volume25
Issue number23
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Cowden Dahl, K. D., Fryer, B. H., Mack, F. A., Compernolle, V., Maltepe, E., Adelman, D. M., Carmeliet, P., & Simon, M. C. (2005). Hypoxia-inducible factors 1α and 2α regulate trophoblast differentiation. Molecular and cellular biology, 25(23), 10479-10491. https://doi.org/10.1128/MCB.25.23.10479-10491.2005