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Loss of ATOH8 leads to defects in murine placenta development, yet its specific functions in self-renewal and differentiation of human trophoblast stem cells (TSCs) remain poorly understood. Here, we reveal that ATOH8 is critical for extravillous trophoblasts (EVTs) formation while being dispensable for the self-renewal of TSCs. We show predominant ATOH8 expression in EVTs compared to syncytiotrophoblasts (STs) and TSCs. Knockdown (KD) of ATOH8 in TSCs does not alter their morphology, proliferation, or self-renewal marker expression, indicating that ATOH8 is not required for TSC maintenance. However, during EVT differentiation, ATOH8 expression gradually increases and its depletion results in pronounced morphological abnormalities, impaired expression of EVT markers, sustained TSC marker expression, and abolished invasive capacity. Conversely, ATOH8 overexpression (OE) under self-renewing conditions modestly induces EVT markers, whereas its OE during ST differentiation disrupts ST formation by reducing cell fusion and aberrantly activating EVT genes. Transcriptomic profiling reveals that the loss of ATOH8 during EVT differentiation disrupts pathways critical for placental development, including extracellular matrix organization and PI3K-AKT signaling. We also show that ATOH8 functions within a cooperative network of EVT regulators, reciprocally regulating their expression and maintaining a transcriptional circuit essential for EVT specification. Collectively, these findings establish ATOH8 as an indispensable regulator of EVT differentiation and invasive function, orchestrating EVT-specific gene programs and pathways alongside other key transcription factors to ensure proper EVT formation.<\/jats:p>","DOI":"10.1038\/s41598-025-22484-3","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:48:14Z","timestamp":1762282094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ATOH8 is crucial for the differentiation of human trophoblast stem cells into extravillous trophoblasts"],"prefix":"10.1038","volume":"15","author":[{"given":"Joudi","family":"Salamah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Salamah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bum-Kyu","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"22484_CR1","doi-asserted-by":"publisher","first-page":"163428","DOI":"10.1242\/dev.163428","volume":"146","author":"MY Turco","year":"2019","unstructured":"Turco, M. 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