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However, this canonical paradigm has never been directly tested using genomic loss-of-function models. Here we show that IFNT is completely dispensable for pregnancy recognition, luteal maintenance, and full-term gestation in cattle. Using CRISPR-Cas9, we generate bovine fibroblasts lacking all functional copies of the multigene\n                    <jats:italic>IFNT<\/jats:italic>\n                    locus for somatic cell nuclear transfer.\n                    <jats:italic>IFNT<\/jats:italic>\n                    -null embryos develop into blastocysts in vitro at normal rates and exhibit typical elongation at day 18 post-transfer without inducing endometrial interferon-stimulated genes. Crucially, these\n                    <jats:italic>IFNT<\/jats:italic>\n                    -null conceptuses successfully prevent luteal regression, establish normal placentation, and progress through full-term gestations, culminating in the birth of healthy female calves. These findings provide the first direct genetic evidence that embryonic IFNT is dispensable for pregnancy recognition and establishment in cattle, fundamentally revising the long-standing model of ruminant reproduction and uncovering alternative embryo-maternal signaling mechanisms.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-78446-4","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:04:43Z","timestamp":1791425083000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pregnancy establishment in cattle without embryonic interferon tau"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5137-2547","authenticated-orcid":false,"given":"Asghar","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeri","family":"Zakhartchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuna","family":"G\u00fcng\u00f6r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"N\u00fcske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6432-1271","authenticated-orcid":false,"given":"Jan B.","family":"St\u00f6ckl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9170-5625","authenticated-orcid":false,"given":"Sarah","family":"Hecken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-7252","authenticated-orcid":false,"given":"Andreas","family":"Hauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5112-9507","authenticated-orcid":false,"given":"Stefan","family":"Krebs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4605-9791","authenticated-orcid":false,"given":"Sven","family":"Reese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Suchowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Friedl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Schwanitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7075-0067","authenticated-orcid":false,"given":"Armin M.","family":"Scholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Blutke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Protschka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"B\u00fcttner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-3211","authenticated-orcid":false,"given":"Thomas","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst-Dieter","family":"Reichenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0430-9510","authenticated-orcid":false,"given":"Eckhard","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"78446_CR1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/2049-1891-5-53","volume":"5","author":"K Brooks","year":"2014","unstructured":"Brooks, K., Burns, G. & Spencer, T. E. Conceptus elongation in ruminants: roles of progesterone, prostaglandin, interferon tau and cortisol. J. Anim. Sci. Biotechnol. 5, 53, https:\/\/doi.org\/10.1186\/2049-1891-5-53 (2014).","journal-title":"J. Anim. Sci. Biotechnol."},{"key":"78446_CR2","doi-asserted-by":"publisher","first-page":"skac123","DOI":"10.1093\/jas\/skac123","volume":"100","author":"DJ Mathew","year":"2022","unstructured":"Mathew, D. J., Peterson, K. D., Senn, L. K., Oliver, M. A. & Ealy, A. D. Ruminant conceptus-maternal interactions: interferon-tau and beyond. J. Anim. Sci. 100, skac123, https:\/\/doi.org\/10.1093\/jas\/skac123 (2022).","journal-title":"J. Anim. Sci."},{"key":"78446_CR3","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/9915814","volume":"2021","author":"A Kowalczyk","year":"2021","unstructured":"Kowalczyk, A., Czerniawska-Pi\u0105tkowska, E. & Wrzeci\u0144ska, M. The importance of interferon-tau in the diagnosis of pregnancy. Biomed. Res Int 2021, 9915814. https:\/\/doi.org\/10.1155\/2021\/9915814 (2021).","journal-title":"Biomed. Res Int"},{"key":"78446_CR4","doi-asserted-by":"publisher","first-page":"3002","DOI":"10.2527\/jas.2013-5882","volume":"91","author":"G Bridges","year":"2013","unstructured":"Bridges, G., Day, M., Geary, T. & Cruppe, L. Triennial Reproduction Symposium: deficiencies in the uterine environment and failure to support embryonic development. J. Anim. Sci. 91, 3002\u20133013 (2013).","journal-title":"J. Anim. Sci."},{"key":"78446_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/2049-1891-4-23","volume":"4","author":"FW Bazer","year":"2013","unstructured":"Bazer, F. W. Pregnancy recognition signaling mechanisms in ruminants and pigs. J. Anim. Sci. Biotechnol. 4, 23, https:\/\/doi.org\/10.1186\/2049-1891-4-23 (2013).","journal-title":"J. Anim. Sci. 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Mechanism of action of interferon-tau in the uterus during early pregnancy. J. Reprod. Fertil. Suppl. 54, 329\u2013339 (1999).","journal-title":"J. Reprod. Fertil. Suppl."},{"key":"78446_CR9","doi-asserted-by":"publisher","first-page":"F11","DOI":"10.1530\/rep-17-0257","volume":"154","author":"FW Bazer","year":"2017","unstructured":"Bazer, F. W. & Thatcher, W. W. Chronicling the discovery of interferon tau. Reproduction 154, F11\u2013f20, https:\/\/doi.org\/10.1530\/rep-17-0257 (2017).","journal-title":"Reproduction"},{"key":"78446_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2025.157035","volume":"196","author":"I Batool","year":"2025","unstructured":"Batool, I., Kausar, R. & Qamar, M. S. Interferon tau in ruminant reproduction: mechanisms of maternal recognition of pregnancy and implications for fertility enhancement. Cytokine 196, 157035. https:\/\/doi.org\/10.1016\/j.cyto.2025.157035 (2025).","journal-title":"Cytokine"},{"key":"78446_CR11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1530\/jrf.0.0710057","volume":"71","author":"J Godkin","year":"1984","unstructured":"Godkin, J., Bazer, F., Thatcher, W. & Roberts, R. Proteins released by cultured day 15\u201316 conceptuses prolong luteal maintenance when introduced into the uterine lumen of cyclic ewes. Reproduction 71, 57\u201364 (1984).","journal-title":"Reproduction"},{"key":"78446_CR12","unstructured":"Lewis, G., Basha, S., Bazer, F., Roberts, R. & Thatcher, W. Proteins originating from bovine and porcine blastocysts. In Proc. Am. Soc. Anim. Sci. (Tucson, AZ), Abstr. 313 (1979)."},{"key":"78446_CR13","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1530\/jrf.0.0650141","volume":"65","author":"J Godkin","year":"1982","unstructured":"Godkin, J., Bazer, F., Moffatt, J., Sessions, F. & Roberts, R. Purification and properties of a major, low molecular weight protein released by the trophoblast of sheep blastocysts at day 13\u201321. Reproduction 65, 141\u2013150 (1982).","journal-title":"Reproduction"},{"key":"78446_CR14","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1530\/jrf.0.0560063","volume":"56","author":"J Martal","year":"1979","unstructured":"Martal, J., Lacroix, M.-C., Loudes, C., Saunier, M. & Wintenberger-Torres, S. Trophoblastin, an antiluteolytic protein present in early pregnancy in sheep. Reproduction 56, 63\u201373 (1979).","journal-title":"Reproduction"},{"key":"78446_CR15","unstructured":"Wilson, M., Lewis, G. & Bazer, F. Proteins of ovine blastocyst origin. In Proc. Soc. Study Reprod. (Quebec, Canada), Abstr. 101A (1979)."},{"key":"78446_CR16","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/330377a0","volume":"330","author":"K Imakawa","year":"1987","unstructured":"Imakawa, K. et al. Interferon-like sequence of ovine trophoblast protein secreted by embryonic trophectoderm. Nature 330, 377\u2013379, https:\/\/doi.org\/10.1038\/330377a0 (1987).","journal-title":"Nature"},{"key":"78446_CR17","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1210\/mend-3-1-127","volume":"3","author":"K Imakawa","year":"1989","unstructured":"Imakawa, K. et al. Molecular cloning and characterization of complementary deoxyribonucleic acids corresponding to bovine trophoblast protein-1: a comparison with ovine trophoblast protein-1 and bovine interferon-\u03b1II. Mol. Endocrinol. 3, 127\u2013139, https:\/\/doi.org\/10.1210\/mend-3-1-127 (1989).","journal-title":"Mol. Endocrinol."},{"key":"78446_CR18","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1016\/j.theriogenology.2014.01.039","volume":"81","author":"H Hirayama","year":"2014","unstructured":"Hirayama, H. et al. 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Intrauterine injection of ovine interferon-tau alters oestrogen receptor and oxytocin receptor expression in the endometrium of cyclic ewes. J. Mol. Endocrinol. 15, 203\u2013220, https:\/\/doi.org\/10.1677\/jme.0.0150203 (1995).","journal-title":"J. Mol. Endocrinol."},{"key":"78446_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.domaniend.2021.106671","volume":"78","author":"R Meidan","year":"2022","unstructured":"Meidan, R. & Basavaraja, R. Interferon-Tau regulates a plethora of functions in the corpus luteum. Domest. Anim. Endocrinol. 78, 106671. https:\/\/doi.org\/10.1016\/j.domaniend.2021.106671 (2022).","journal-title":"Domest. Anim. Endocrinol."},{"key":"78446_CR22","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abe4627","volume":"14","author":"M Shemesh","year":"2021","unstructured":"Shemesh, M., Lochte, S., Piehler, J. & Schreiber, G. IFNAR1 and IFNAR2 play distinct roles in initiating type I interferon-induced JAK-STAT signaling and activating STATs. Sci. 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