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Two distinct types of endometrial epithelial cells, the luminal (LE) and glandular (GE) epithelial cells play different functional roles during this physiological process. Previously, we have reported that Notch signaling plays multiple roles in embryo implantation, decidualization, and postpartum repair. Here, using\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/7949732\/\">the<\/jats:ext-link>\n                    uterine epithelial\u2010specific Ltf\u2010iCre, we showed that Notch1 signaling over\u2010activation in the endometrial epithelium caused dysfunction of the epithelium during the estrous cycle, resulting in hyper\u2010proliferation. During pregnancy, it further led to dysregulation of estrogen and progesterone signaling, resulting in infertility in these animals. Using 3D organoids, we showed that over\u2010activation of Notch1 signaling increased the proliferative potential of both LE and GE cells and reduced the difference in transcription profiles between them, suggesting disrupted differentiation of the uterine epithelium. In addition, we demonstrated that both canonical and non\u2010canonical Notch signaling contributed to the hyper\u2010proliferation of GE cells, but only the non\u2010canonical pathway was involved with estrogen sensitivity in the GE cells. These findings provided insights into the effects of Notch1 signaling on the proliferation, differentiation, and function of the uterine epithelium. This study demonstrated the important roles of Notch1 signaling in regulating hormone response and differentiation of endometrial epithelial cells and provides an opportunity for future studies in estrogen\u2010dependent diseases, such as endometriosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201868rr","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T09:09:39Z","timestamp":1685437779000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Aberrant activation of Notch1 signaling in the mouse uterine epithelium promotes hyper\u2010proliferation by increasing estrogen sensitivity"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4424-1645","authenticated-orcid":false,"given":"Qi\u2010Xin","family":"Xu","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine South China Agricultural University  Guangzhou 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