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While amplification of this signaling is essential for FSH\u2010dependent follicle maturation, the molecular drivers remain less well\u2010understood. Through integrated single\u2010cell and spatial transcriptomic analyses, we identified\n                    <jats:italic>Fosl2<\/jats:italic>\n                    as an FSH\u2010responsive transcription factor exhibiting a dynamic temporal expression pattern that closely mirrored that of the\n                    <jats:italic>Fshr<\/jats:italic>\n                    . In vitro\n                    <jats:italic>Fosl2<\/jats:italic>\n                    knockdown resulted in notable reductions in granulosa cell proliferation, induced apoptosis, and disrupted FSH\u2010dependent follicle maturation. In vivo studies using conditional\n                    <jats:italic>Fosl2<\/jats:italic>\n                    knockout demonstrated a complete halt in FSH\u2010dependent follicle maturation and resultant infertility. Mechanistic exploration unveiled that FSH\/FSHR initiates\n                    <jats:italic>Fosl2<\/jats:italic>\n                    transcription via the cAMP\u2010PKA\u2010CREB cascade, while FOSL2 protein, in turn, acts as a direct transcriptional activator of the\n                    <jats:italic>Fshr<\/jats:italic>\n                    gene itself, as well as estrogen\u2010synthesis genes (\n                    <jats:italic>Cyp11a1<\/jats:italic>\n                    and\n                    <jats:italic>Cyp19a1<\/jats:italic>\n                    ), thereby establishing a positive feedback loop for FSH\/FSHR signaling. Cross\u2010species validation demonstrated evolutionary conservation of this loop, with\n                    <jats:italic>Fosl2<\/jats:italic>\n                    knockdown impairing FSH\/FSHR signaling in sheep and human. Our findings identify a\n                    <jats:italic>Fosl2<\/jats:italic>\n                    \u2010centered feedback loop essential for amplifying FSH\/FSHR, underscoring\n                    <jats:italic>Fosl2<\/jats:italic>\n                    \u2019s critical role in reproduction.\n                  <\/jats:p>","DOI":"10.1002\/advs.75223","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T19:18:58Z","timestamp":1775762338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fosl2 Regulates FSH\u2010Dependent Follicle Maturation Through Feedback Amplification of FSH\/FSHR Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Hongru","family":"Shi","sequence":"first","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education College of Animal Sciences and Technology Shennongjia Science and Technology Innovation Center, Shennongjia Field Comprehensive Scientific Observation and Research Station of the Ministry of Agriculture and Rural Affairs Huazhong Agricultural University Wuhan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoli","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Maternal and Child Health Hospital of Hubei Province  Wuhan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaohong","family":"Ran","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education College of Animal Sciences and Technology Shennongjia Science and Technology Innovation Center, Shennongjia Field Comprehensive Scientific Observation and Research Station of the Ministry of Agriculture and Rural Affairs Huazhong Agricultural University Wuhan P. R. 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