{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:10:44Z","timestamp":1789056644922,"version":"build-2803163510"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["HD106120"],"award-info":[{"award-number":["HD106120"]}]},{"name":"NCI","award":["CA283677"],"award-info":[{"award-number":["CA283677"]}]},{"DOI":"10.13039\/100000066","name":"NIEHS","doi-asserted-by":"crossref","award":["Z1AES103311-01"],"award-info":[{"award-number":["Z1AES103311-01"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["HD118485-01A1"],"award-info":[{"award-number":["HD118485-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Successful implantation requires precise coordination of uterine epithelial receptivity, stromal decidualization, and immune homeostasis during a narrow peri-implantation window. Although retinoic acid (RA) signaling has been implicated in female reproduction, the endogenous and isoform-specific roles of retinoic acid receptors (RARs) remain poorly defined. Here, we combined isoform-specific genetic mouse models, transcriptomic profiling, and functional studies in mouse and human stromal cells to determine how RAR signaling regulates early pregnancy. We found that RARG is the dominant RAR isoform required for female fertility in mice, as its deletion severely impaired implantation, whereas combined loss of all RAR isoforms caused complete reproductive failure. RAR deficiency disrupted multiple sequential reproductive processes, including sperm transport and fertilization, suppression of uterine estrogen receptor activity, acquisition of stromal decidualization competence, and maintenance of uterine immune homeostasis. Transcriptomic analyses identified conserved epithelial and mesenchymal programs altered across independent RAR-deficient mouse models and revealed significant overlap with endometrial gene signatures from women with recurrent implantation failure. In human endometrial stromal cells, suppression of the RARA isoform consistently disrupted decidualization across three independent primary cell lines and an immortalized cell model. Together, these findings identify RAR signaling as a critical regulator of early pregnancy and reveal conserved, isoform-specific functions required for early pregnancy.<\/jats:p>","DOI":"10.1172\/jci206283","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:00:18Z","timestamp":1789056018000},"source":"Crossref","is-referenced-by-count":0,"title":["Retinoic acid receptor signaling orchestrates uterine receptivity, decidual competence, and immune homeostasis during early pregnancy"],"prefix":"10.1172","author":[{"given":"Yan","family":"Yin","sequence":"first","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Y.","family":"So","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Wolf","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Robles Pinos","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-7660","authenticated-orcid":true,"given":"Meade","family":"Haller","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjie","family":"Shang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Center for Cardiovascular R, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia C.","family":"Hewitt","sequence":"additional","affiliation":[{"name":"Pregnancy & Female Reproduction Group, Reproductive and Developmental Biolo, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Tak","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent M.","family":"Bany","sequence":"additional","affiliation":[{"name":"Department of Physiology, Southern Illinois University School of Medicine, Carbondale, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Y.","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengcheng","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Center for Cardiovascular R, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9480-7336","authenticated-orcid":true,"given":"Francesco J.","family":"DeMayo","sequence":"additional","affiliation":[{"name":"Pregnancy & Female Reproduction Group, Reproductive and Developmental Biolo, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,10]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/206283\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:00:20Z","timestamp":1789056020000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/206283"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":0,"alternative-id":["10.1172\/JCI206283"],"URL":"https:\/\/doi.org\/10.1172\/jci206283","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}