Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability
Open accessAbstract
Inositol requiring enzyme-1 (IRE1), a protein located on the endoplasmic reticulum (ER) membrane, is highly conserved from yeast to humans. This protein is activated during ER stress and induces cellular adaptive responses to the stress. In mice, IRE1α inactivation results in widespread developmental defects, leading to embryonic death after 12.5 days of gestation. However, the cause of this embryonic lethality is not fully understood. Here, by using in vivo imaging analysis and conventional knockout mice, respectively, we showed that IRE1α was activated predominantly in the placenta and that loss of IRE1α led to reduction in vascular endothelial growth factor-A and severe dysfunction of the labyrinth in the placenta, a highly developed tissue of blood vessels. We also used a conditional knockout strategy to demonstrate that IRE1 α-deficient embryos supplied with functionally normal placentas can be born alive. Fetal liver hypoplasia thought to be responsible for the embryonic lethality of IRE1 α-null mice was virtually absent in rescued IRE1 α-null pups. These findings reveal that IRE1α plays an essential function in extraembryonic tissues and highlight the relationship of physiological ER stress and angiogenesis in the placenta during pregnancy in mammals.
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The IRE1 pathway is essential for normal placental development in mice; knockout leads to downregulation of VEGF and abnormal angiogenesis within the labyrinth.
“Manipulations in mice have confirmed that the IRE1 pathway is essential for normal placental development, for knockout leads to downregulation of VEGF and abnormal angiogenesis within the labyrinth (273).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [273]
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- Authors
- Iwawaki, T., Akai, R., Yamanaka, S., & Kohno, K.
- Affiliations
- Japan Science and Technology Agency (JP)
- RIKEN (JP)
- Kyoto University (JP)
- Nara Institute of Science and Technology (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-29
- Volume
- 106
- Issue
- 39
- Pages
- 16657-16662
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2757843
- OpenAlex
- W2122345674
- Cited by
- 377
- References
- 55
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 27 · 2023: 30 · 2022: 27 · 2021: 30 · 2020: 29 · 2019: 26 · 2018: 23 · 2017: 25 · 2016: 18 · 2015: 20 · 2014: 17 · 2013: 27 · 2012: 22
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Suzuken Memorial Foundation
- Takeda Science Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (14037240)
- RIKEN
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- IRE1α, placenta, placental development, embryonic lethality, endoplasmic reticulum stress, VEGF-A, placental labyrinth, angiogenesis, conditional knockout mice, extraembryonic tissues
- MeSH terms
- Animals, Embryo, Mammalian, Endoplasmic Reticulum, Endoribonucleases, Female, Membrane Proteins, Mice, Transgenic, Placenta, Pregnancy, Protein Serine-Threonine Kinases, Mice, Knockout, Embryo Loss, Embryonic Development, Mice
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