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The tumor suppressor gene NF2, moesin\u2010ezrin\u2010radixin like (MERLIN) tumor suppressor (Nf2) is expressed in all 3 germ layers during mouse development and its homozygous deletion causes embryonic lethality. People with heterozygous NF2 mutations typically develop Schwann cell tumors, especially vestibular schwannoma, but the specific role of NF2 in human embryonic development is unclear. Here, human induced pluripotent stem cells (hiPSCs) are used to demonstrate that NF2 is essential for endoderm specification and formation in humans. Although endoderm differentiation is not impaired in hiPSCs with heterozygous NF2 mutation, NF2 knockout (NF2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) abolished the capacity to form endoderm in vitro, confirmed by loss of expression of endoderm\u2010related genes and proteins, or teratomas in vivo. This defect is mediated by the nuclear translocation of yes\u2010associated protein 1 (YAP1), a transcription co\u2010activator regulating lineage fate via the Hippo pathway and subsequent YAP1\u2010mediated shutdown of Activin\/Nodal signaling. Endoderm formation can be rescued via YAP1 knockdown or forced re\u2010expression of NF2 in NF2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells. Taken together, the essential role of NF2 during endoderm specification in human embryogenesis as a regulator of YAP1 is reported.\n                  <\/jats:p>","DOI":"10.1002\/advs.202410909","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:28:05Z","timestamp":1739251685000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>NF2<\/i>\n                    is Essential for Human Endoderm Development"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-502X","authenticated-orcid":false,"given":"Minjin","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Stanford University School of Medicine  Stanford CA 94305 USA"},{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Massachusetts Eye and Ear and Harvard Medical School  Boston MA 02114 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8887-7039","authenticated-orcid":false,"given":"Dongjun","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Stanford University School of Medicine  Stanford CA 94305 USA"},{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Massachusetts Eye and Ear and Harvard Medical School  Boston MA 02114 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1988-3830","authenticated-orcid":false,"given":"Preetida","family":"Bhetariya","sequence":"additional","affiliation":[{"name":"Bioinformatics Core Harvard T.H. 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