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CRISPR\/Cas9 knockout of <jats:italic>Pigl<\/jats:italic> and <jats:italic>Pigf<\/jats:italic> in mouse trophoblast stem cells (mTSCs) confirms the role of these GPI enzymes in syncytiotrophoblast differentiation. Mechanistically, impaired GPI-AP generation induces an excessive unfolded protein response (UPR) in the ER in mTSCs growing in stem cell conditions, akin to what is observed in human preeclampsia.\u00a0Upon differentiation, the impairment of the GPI pathway hinders the induction of WNT signaling for early SynT-II development.\u00a0Remarkably, the transcriptomic profile of <jats:italic>Pigl<\/jats:italic>- and <jats:italic>Pigf<\/jats:italic>-deficient cells separates human patient placental samples into preeclampsia and control groups, suggesting an involvement of <jats:italic>Pigl<\/jats:italic> and <jats:italic>Pigf<\/jats:italic> in establishing a preeclamptic gene signature. Our study unveils the pivotal role of GPI biosynthesis in early placentation and uncovers a new preeclampsia gene expression profile associated with mutations in the GPI biosynthesis pathway, providing novel molecular insights into placental development with implications for enhanced patient stratification and timely interventions.<\/jats:p>","DOI":"10.1007\/s00018-024-05284-2","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T10:04:17Z","timestamp":1717149857000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development"],"prefix":"10.1007","volume":"81","author":[{"given":"Andrea","family":"\u00c1lvarez-S\u00e1nchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Grinat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Doria-Borrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maravillas","family":"Mellado-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9rica","family":"Pedrera-Alc\u00f3cer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Malenchini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Meseguer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Hemberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5594-1607","authenticated-orcid":false,"given":"Vicente","family":"P\u00e9rez-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,31]]},"reference":[{"issue":"1","key":"5284_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41576-019-0169-4","volume":"21","author":"M Hemberger","year":"2020","unstructured":"Hemberger M, Hanna CW, Dean W (2020) Mechanisms of early placental development in mouse and humans. 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