{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:30:50Z","timestamp":1793651450182,"version":"4.5.1"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"39","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,9,29]]},"abstract":"<jats:p>\n                    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\u03b1 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\u03b1 was activated predominantly in the placenta and that loss of IRE1\u03b1 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\n                    <jats:italic toggle=\"yes\">IRE1<\/jats:italic>\n                    \u03b1-deficient embryos supplied with functionally normal placentas can be born alive. Fetal liver hypoplasia thought to be responsible for the embryonic lethality of\n                    <jats:italic toggle=\"yes\">IRE1<\/jats:italic>\n                    \u03b1-null mice was virtually absent in rescued\n                    <jats:italic toggle=\"yes\">IRE1<\/jats:italic>\n                    \u03b1-null pups. These findings reveal that IRE1\u03b1 plays an essential function in extraembryonic tissues and highlight the relationship of physiological ER stress and angiogenesis in the placenta during pregnancy in mammals.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0903775106","type":"journal-article","created":{"date-parts":[[2009,9,16]],"date-time":"2009-09-16T00:10:03Z","timestamp":1253059803000},"page":"16657-16662","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":364,"title":["Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability"],"prefix":"10.1073","volume":"106","author":[{"given":"Takao","family":"Iwawaki","sequence":"first","affiliation":[{"name":"Iwawaki Initiative Research Unit, Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;"},{"name":"Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, Japan;"},{"name":"Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko","family":"Akai","sequence":"additional","affiliation":[{"name":"Iwawaki Initiative Research Unit, Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;"},{"name":"Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Kohno","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; 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