Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability

TLDR

IRE1α is a highly conserved ER membrane protein that is activated during ER stress to trigger adaptive responses, and its inactivation in mice causes widespread developmental defects leading to embryonic death after 12.5 days of gestation. The study aims to determine the underlying cause of embryonic lethality observed in IRE1α‑null mice. Using in vivo imaging and conventional knockout mice, the authors showed that IRE1α is predominantly activated in the placenta, where its loss reduces VEGF‑A and disrupts labyrinthine vascular development, and that conditional knockout of IRE1α in embryos with normal placentas allows live birth. Rescued IRE1α‑null pups lacked fetal liver hypoplasia, demonstrating that IRE1α’s essential role lies in extraembryonic tissues and linking physiological ER stress to placental angiogenesis during pregnancy.

Abstract

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, IRE1alpha 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 IRE1alpha was activated predominantly in the placenta and that loss of IRE1alpha 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 IRE1alpha-deficient embryos supplied with functionally normal placentas can be born alive. Fetal liver hypoplasia thought to be responsible for the embryonic lethality of IRE1alpha-null mice was virtually absent in rescued IRE1alpha-null pups. These findings reveal that IRE1alpha plays an essential function in extraembryonic tissues and highlight the relationship of physiological ER stress and angiogenesis in the placenta during pregnancy in mammals.