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The surface of the placenta facing the maternal blood is formed by a single giant multinucleate cell: the syncytiotrophoblast. The syncytiotrophoblast is formed and maintained via fusion of progenitor cytotrophoblasts. Cell-cell fusion is a tightly regulated process, and in non-trophoblastic cells is accompanied by stereotypical alterations in cell shape by cells that have attained fusion-competence. The most prominent feature is the formation of actin-based membrane protrusions, but whether stereotypic morphological changes occur in fusion-competent cytotrophoblasts has not been characterized. Using a human placental explant model and trophoblast organoids, we identify microvilliation as a morphological feature that is enriched prior to fusion of cytotrophoblasts. Disruption of microvilli using an inhibitor of the actin-membrane cross-linker protein ezrin blocked cytotrophoblast fusion in both models. We provide evidence that cytotrophoblast microvilli are enriched in early endosomes and a pro-fusogenic protein. Thus, we propose that the polarized assembly of microvillar domains is crucial for mediating efficient syncytiotrophoblast development.<\/jats:p>","DOI":"10.1242\/dev.204619","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T05:53:06Z","timestamp":1744350786000},"source":"Crossref","is-referenced-by-count":5,"title":["Placental cytotrophoblast microvillar stabilization is required for cell-cell fusion"],"prefix":"10.1242","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9465-6064","authenticated-orcid":false,"given":"Wendy K.","family":"Duan","sequence":"first","affiliation":[{"name":"University of Alberta 1 Department of Physiology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2235-4569","authenticated-orcid":false,"given":"Sumaiyah Z.","family":"Shaha","sequence":"additional","affiliation":[{"name":"University of Alberta 1 Department of Physiology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8423-6429","authenticated-orcid":false,"given":"Juan F.","family":"Garcia Rivas","sequence":"additional","affiliation":[{"name":"University of Alberta 2 Department of Obstetrics and Gynecology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6642-7527","authenticated-orcid":false,"given":"Bethan L.","family":"Wilson","sequence":"additional","affiliation":[{"name":"University of Alberta 1 Department of Physiology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8027-2206","authenticated-orcid":false,"given":"Khushali J.","family":"Patel","sequence":"additional","affiliation":[{"name":"University of Alberta 2 Department of Obstetrics and Gynecology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-4103","authenticated-orcid":false,"given":"Ivan K.","family":"Domingo","sequence":"additional","affiliation":[{"name":"University of Alberta 2 Department of Obstetrics and Gynecology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3203-2897","authenticated-orcid":false,"given":"Meghan R.","family":"Riddell","sequence":"additional","affiliation":[{"name":"University of Alberta 1 Department of Physiology , , Edmonton, Alberta T6G 2S2,","place":["Canada"]},{"name":"University of Alberta 2 Department of Obstetrics and Gynecology , , Edmonton, Alberta T6G 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