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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,18]]},"abstract":"<jats:p>\n                    Follicle-stimulating hormone (FSH) acts by binding to FSHRs expressed on ovarian granulosa cells and produces estradiol. FSH is essential for female fertility because mice lacking FSH (\n                    <jats:italic>Fshb KO<\/jats:italic>\n                    ) are anestrous and infertile. Although several in vitro cell culture and ex vivo approaches combined with pharmacological hormone treatment were used to identify FSH-regulated genes, how FSH orchestrates ovarian gene networks in vivo has not been investigated. Whether FSH-regulated genes display estrous stage\u2013specific expression changes has also not been studied. Here, we functionally rescued\n                    <jats:italic>Fshb<\/jats:italic>\n                    null mice with a gonadotrope-targeted\n                    <jats:italic>HFSHB<\/jats:italic>\n                    transgene and performed RNA-Seq analysis on ovarian RNAs obtained from FSH-intact (\n                    <jats:italic>WT<\/jats:italic>\n                    ), FSH-deficient (\n                    <jats:italic>Fshb KO<\/jats:italic>\n                    ), and FSH-rescue (\n                    <jats:italic>\n                      HFSHB\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    rescue) mice. By comparing\n                    <jats:italic>WT<\/jats:italic>\n                    vs.\n                    <jats:italic>Fshb KO<\/jats:italic>\n                    and\n                    <jats:italic>Fshb KO<\/jats:italic>\n                    vs.\n                    <jats:italic>\n                      HFSHB\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    rescue ovarian gene expression datasets, we identified FSH-responsive genes in vivo. Cross interrogation of these datasets further allowed us to identify several transcription factors (TFs) and RNA-binding proteins specific to FSH-regulated genes. In an independent set of experiments, we performed RNA-Seq analysis on ovarian RNAs from mice in diestrous (DE), proestrous (PE), and estrous (E) and identified estrous stage\u2013specific ovarian gene expression patterns. Interestingly, many of the FSH-regulated TFs themselves were estrous-stage specifically expressed. We found that ESR2 and GATA6, two known FSH-responsive TFs, and their target genes are reciprocally regulated with distinct patterns of expression in estrous stages. Together, our in vivo models and RNA-Seq analyses identify FSH-regulated ovarian genes in specific estrous stages that are under transcriptional and posttranscriptional control.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2411977122","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T15:04:36Z","timestamp":1739199876000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Identification of FSH-regulated and estrous stage\u2013specific transcriptional networks in mouse ovaries"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-6889","authenticated-orcid":false,"given":"Kathryn","family":"Walters","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus","place":["Aurora"]},{"name":"RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus","place":["Aurora"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7346-3052","authenticated-orcid":false,"given":"Amber","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus","place":["Aurora"]},{"name":"RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus","place":["Aurora"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghui","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus","place":["Aurora"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2800-3487","authenticated-orcid":false,"given":"Mark","family":"Larsen","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus","place":["Aurora"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelanjan","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus","place":["Aurora"]},{"name":"RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus","place":["Aurora"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7666-5493","authenticated-orcid":false,"given":"T. Rajendra","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus","place":["Aurora"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-47912-7.00002-0"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.50.070181.002341"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-44441-3_3"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0297-201"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.139.7.6111"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321404111"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.08.031"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.vh.2018.01.009"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41350"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20200167"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-02062-9_2"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00087"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13459"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.142.7.8279"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep28132"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.vh.2018.01.019"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2018.02.012"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-02062-9_1"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-00302-y"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00550-0"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom5031228"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmb2.12575"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77239"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqae054"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.202170"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2022.10.012"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom13101477"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-023-03437-1"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa245"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2202"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.2741\/3915"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00586"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0334-5"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00930"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31222"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1410"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1969"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.vh.2018.01.014"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.138.8.5350"},{"key":"e_1_3_5_41_2","first-page":"8","article-title":"Selecting female mice in estrus and checking plugs","author":"Behringer R.","year":"2016","unstructured":"R. Behringer, M. Gertsenstein, K. V. Nagy, A. Nagy, Selecting female mice in estrus and checking plugs. Cold Spring Harb. Protoc. 2016, 8 (2016).","journal-title":"Cold Spring Harb. Protoc."},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2023.111971"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1087"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7563.1"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_5_47_2","unstructured":"K. Walters Discovery of FSH-regulated and estrus stage-specific transcriptional networks in mouse ovaries. Gene Expression Omnibus. https:\/\/www.ncbi.xyz\/geo\/query\/acc.cgi?acc=GSM8288804. Deposited 23 May 2024."}],"updated-by":[{"DOI":"10.1073\/pnas.2504347122","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2411977122","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2411977122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T14:01:06Z","timestamp":1742565666000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2411977122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,10]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,2,18]]}},"alternative-id":["10.1073\/pnas.2411977122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2411977122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,10]]},"assertion":[{"value":"2024-06-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2411977122"}}