Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability
Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability
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DOI：
10.1073/pnas.0903775106
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发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Kohno, Kenji
中科院分区：
文献类型：
--
作者：
Iwawaki, Takao;Akai, Ryoko;Kohno, Kenji
肌醇需要酶-1(IRE1)是一种位于内质网(ER)膜上的蛋白质，从酵母到人类都高度保守。该蛋白在内质网应激过程中被激活，并诱导细胞对应激的适应性反应。在小鼠中，IRE1α失活会导致广泛的发育缺陷，导致怀孕12.5天后的胚胎死亡。然而，这种胚胎致死的原因还没有完全弄清楚。在这里，通过分别使用活体成像分析和传统的基因敲除小鼠，我们发现IRE1α主要在胎盘中被激活，并且IRE1α的缺失导致血管内皮生长因子-A的减少和胎盘迷路的严重功能障碍，胎盘是高度发达的血管组织。我们还使用了条件基因敲除策略来证明，提供功能正常的胎盘的IRE1α缺陷胚胎可以活着出生。胎肝发育不良被认为是导致IRE1α缺失小鼠胚胎死亡的原因，但在获救的IRE1阿尔法缺失幼鼠中几乎没有。这些发现揭示了IRE1α在胚胎外组织中的重要功能，并强调了哺乳动物妊娠期间生理性内质网应激与胎盘血管生成的关系。
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, IRE1 alpha 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 IRE1 alpha was activated predominantly in the placenta and that loss of IRE1 alpha 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 alpha-deficient embryos supplied with functionally normal placentas can be born alive. Fetal liver hypoplasia thought to be responsible for the embryonic lethality of IRE1 alpha-null mice was virtually absent in rescued IRE1 alpha-null pups. These findings reveal that IRE1 alpha plays an essential function in extraembryonic tissues and highlight the relationship of physiological ER stress and angiogenesis in the placenta during pregnancy in mammals.