Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation.
Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1alpha and HIF2alpha, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIFalpha and HIFbeta (ARNT) subunits. Placentas from Arnt-/- and Hif1alpha-/- Hif2alpha-/- 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 Hifalpha, 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.
Cowden Dahl
Karen D
KD
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.
Fryer
Benjamin H
BH
Mack
Fiona A
FA
Compernolle
Veerle
V
Maltepe
Emin
E
Adelman
David M
DM
Carmeliet
Peter
P
Simon
M Celeste
MC
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D015726:Giant Cells / Q000166:cytology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010920:Placenta / Q000002:abnormalities / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse