{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:46:22Z","timestamp":1791308782468,"version":"4.3.1"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,9,28]],"date-time":"2012-09-28T00:00:00Z","timestamp":1348790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We recently reported the first evidence of placental endoplasmic reticulum (ER) stress in the pathophysiology of human intrauterine growth restriction. Here, we used a mouse model to investigate potential underlying mechanisms. <jats:italic>Eif2s1<\/jats:italic><jats:sup><jats:italic>tm1RjK<\/jats:italic><\/jats:sup> mice, in which Ser51 of eukaryotic initiation factor 2 subunit alpha (eIF2\u03b1) is mutated, display a 30% increase in basal translation. In <jats:italic>Eif2s1<\/jats:italic><jats:sup><jats:italic>tm1RjK<\/jats:italic><\/jats:sup> placentas, we observed increased ER stress and anomalous accumulation of glycoproteins in the endocrine junctional zone (Jz), but not in the labyrinthine zone where physiological exchange occurs. Placental and fetal weights were reduced by 15% (97 mg to 82 mg, <jats:italic>p<\/jats:italic> &lt; 0.001) and 20% (1009 mg to 798 mg, <jats:italic>p<\/jats:italic> &lt; 0.001), respectively. To investigate whether ER stress affects bioactivity of secreted proteins, mouse embryonic fibroblasts (MEFs) were derived from <jats:italic>Eif2s1<\/jats:italic><jats:sup><jats:italic>tm1RjK<\/jats:italic><\/jats:sup> mutants. These MEFs exhibited ER stress, grew 50% slower, and showed reduced Akt\u2013mTOR signalling compared to wild\u2010type cells. Conditioned medium (CM) derived from <jats:italic>Eif2s1<\/jats:italic><jats:sup><jats:italic>tm1RjK<\/jats:italic><\/jats:sup> MEFs failed to maintain trophoblast stem cells in a progenitor state, but the effect could be rescued by exogenous application of FGF4 and heparin. In addition, ER stress promoted accumulation of pro\u2010Igf2 with altered glycosylation in the CM without affecting cellular levels, indicating that the protein failed to be processed after release. Igf2 is the major growth factor for placental development; indeed, activity in the Pdk1\u2013Akt\u2013mTOR pathways was decreased in <jats:italic>Eif2s1<\/jats:italic><jats:sup><jats:italic>tm1RjK<\/jats:italic><\/jats:sup> placentas, indicating loss of Igf2 signalling. Furthermore, we observed premature differentiation of trophoblast progenitors at E9.5 in mutant placentas, consistent with the <jats:italic>in vitro<\/jats:italic> results and with the disproportionate development of the labyrinth and Jz seen in placentas at E18.5. Similar disproportion has been reported in the <jats:italic>Igf2<\/jats:italic>\u2010null mouse. These results demonstrate that ER stress adversely affects placental development, and that modulation of post\u2010translational processing, and hence bioactivity, of secreted growth factors contributes to this effect. Placental dysmorphogenesis potentially affects fetal growth through reduced exchange capacity. Copyright \u00a9 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4068","type":"journal-article","created":{"date-parts":[[2012,6,25]],"date-time":"2012-06-25T11:30:19Z","timestamp":1340623819000},"page":"554-564","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction"],"prefix":"10.1002","volume":"228","author":[{"given":"Hong wa","family":"Yung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Hemberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica D","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire 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