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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,9]]},"abstract":"<jats:p>\n                    Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition\u2013mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal\u2013fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of\n                    <jats:italic>Tfeb<\/jats:italic>\n                    compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen\n                    <jats:italic>ERVFRD-1<\/jats:italic>\n                    in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth\u2013restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2404062121","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T12:55:15Z","timestamp":1720184115000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["TFEB safeguards trophoblast syncytialization in humans and mice"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4314-9687","authenticated-orcid":false,"given":"Wanshan","family":"Zheng","sequence":"first","affiliation":[{"name":"Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, Women and Children\u2019s Hospital, School of Medicine, Xiamen 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effect of IFNG (interferon gamma)-induced autophagy depends on HMOX1 (heme oxygenase 1)-mediated increase in intracellular calcium levels and modulation of PPP3\/calcineurin-TFEB (transcription factor EB) axis","volume":"14","author":"Singh N.","year":"2018","unstructured":"N. Singh , Antimycobacterial effect of IFNG (interferon gamma)-induced autophagy depends on HMOX1 (heme oxygenase 1)-mediated increase in intracellular calcium levels and modulation of PPP3\/calcineurin-TFEB (transcription factor EB) axis. 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Zheng Y. Zhang TFEB safeguards trophoblast syncytialization in humans and mice. NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE252254. Deposited 31 December 2023."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2404062121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T14:40:08Z","timestamp":1720708808000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2404062121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,5]]},"references-count":48,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2024,7,9]]}},"alternative-id":["10.1073\/pnas.2404062121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2404062121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,5]]},"assertion":[{"value":"2024-02-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2404062121"}}