{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:25:19Z","timestamp":1781915119458,"version":"3.54.5"},"reference-count":42,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T00:00:00Z","timestamp":1583971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CIHR-152308"],"award-info":[{"award-number":["CIHR-152308"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-133394"],"award-info":[{"award-number":["MOP-133394"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-162343"],"award-info":[{"award-number":["PJT-162343"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["2015\u201305178"],"award-info":[{"award-number":["2015\u201305178"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG029531"],"award-info":[{"award-number":["AG029531"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG056046"],"award-info":[{"award-number":["AG056046"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Follicle-stimulating hormone (FSH), an essential regulator of mammalian fertility, is synthesized by pituitary gonadotrope cells in response to activins. In mice, activins signal via SMAD3, SMAD4, and FOXL2 to regulate transcription of the FSH\u03b2 subunit (Fshb) gene. Gonadotrope-specific deletion of Foxl2, alone or in combination with Smad4, renders mice FSH-deficient. Whether human FSHB expression is similarly regulated is not known. Here, we used a combination of transgenic and conditional knockout mouse strains to assess the roles of activins, FOXL2, and SMAD4 in regulation of the human FSHB gene. First, we cultured pituitaries from mice harboring a human FSHB transgene (hFSHB mice) and measured both murine Fshb and human FSHB messenger ribonucleic acid (mRNA) expression in response to exogenous activins or two antagonists of endogenous activin-like signaling (follistatin-288 and SB431542). Both murine Fshb and human FSHB expression were stimulated by activins and reduced by the inhibitors. Next, we analyzed human FSHB expression in hFSHB mice carrying floxed Foxl2 and Smad4 alleles. Cre-mediated ablation of FOXL2 and SMAD4 strongly reduced basal and activin-stimulated murine Fshb and human FSHB expression in cultured pituitaries. Finally, the hFSHB transgene was previously shown to rescue FSH production and fertility in Fshb knockout mice. However, gonadotrope-specific Foxl2\/Smad4 knockout females carrying the hFSHB transgene have significantly reduced murine Fshb and human FSHB pituitary mRNA levels and are hypogonadal. Collectively, these data suggest that similar to Fshb regulation in mice, FOXL2 and SMAD4 play essential roles in human FSHB expression.<\/jats:p>","DOI":"10.1210\/endocr\/bqaa045","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T12:47:42Z","timestamp":1584622062000},"source":"Crossref","is-referenced-by-count":16,"title":["Human Follicle-Stimulating Hormone \u00df Subunit Expression Depends on FOXL2 and SMAD4"],"prefix":"10.1210","volume":"161","author":[{"given":"Luisina","family":"Ongaro","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauthier","family":"Schang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T Rajendra","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Treier","sequence":"first","affiliation":[{"name":"Max-Delbr\u00fcck Center for Molecular Medicine (MDC), Genetics of Metabolic and Reproductive Disorders, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu-Xia","family":"Deng","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, University of Macau, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Boehm","sequence":"first","affiliation":[{"name":"Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-5586","authenticated-orcid":false,"given":"Daniel J","family":"Bernard","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,3,12]]},"reference":[{"issue":"2","key":"2020052516194860000_CIT0001","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ng0297-201","article-title":"Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility","volume":"15","author":"Kumar","year":"1997","journal-title":"Nat Genet."},{"issue":"5","key":"2020052516194860000_CIT0002","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1089\/dna.1.1989.8.339","article-title":"Isolation and characterization of the gene encoding the beta-subunit of rat follicle-stimulating hormone","volume":"8","author":"Gharib","year":"1989","journal-title":"Dna."},{"issue":"3","key":"2020052516194860000_CIT0003","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1210\/mend.15.3.0603","article-title":"Three-dimensional structure of human follicle-stimulating hormone","volume":"15","author":"Fox","year":"2001","journal-title":"Mol Endocrinol."},{"issue":"2","key":"2020052516194860000_CIT0004","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1210\/edrv-9-2-267","article-title":"Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone","volume":"9","author":"Ying","year":"1988","journal-title":"Endocr Rev."},{"issue":"1-2","key":"2020052516194860000_CIT0005","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0014-5793(98)00954-5","article-title":"The L45 loop in type I receptors for TGF-beta family members is a critical determinant in specifying Smad isoform activation","volume":"434","author":"Persson","year":"1998","journal-title":"FEBS Lett."},{"key":"2020052516194860000_CIT0006","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/1477-7827-4-52","article-title":"Activin B can signal through both ALK4 and ALK7 in gonadotrope cells","volume":"4","author":"Bernard","year":"2006","journal-title":"Reprod Biol Endocrinol."},{"issue":"6","key":"2020052516194860000_CIT0007","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1074\/jbc.M116.759167","article-title":"SMAD3 regulates follicle-stimulating hormone synthesis by pituitary gonadotrope cells in vivo","volume":"292","author":"Li","year":"2017","journal-title":"J Biol Chem."},{"issue":"6","key":"2020052516194860000_CIT0008","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00432-X","article-title":"Mechanisms of TGF-beta signaling from cell membrane to the nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell."},{"issue":"6520","key":"2020052516194860000_CIT0009","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/374356a0","article-title":"Different phenotypes for mice deficient in either activins or activin receptor type II","volume":"374","author":"Matzuk","year":"1995","journal-title":"Nature."},{"issue":"3","key":"2020052516194860000_CIT0010","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1210\/me.2012-1286","article-title":"Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice","volume":"27","author":"Tran","year":"2013","journal-title":"Mol Endocrinol."},{"issue":"8","key":"2020052516194860000_CIT0011","doi-asserted-by":"crossref","first-page":"3396","DOI":"10.1096\/fj.14-249532","article-title":"Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2","volume":"28","author":"Fortin","year":"2014","journal-title":"Faseb J."},{"issue":"7","key":"2020052516194860000_CIT0012","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1210\/en.2018-00100","article-title":"Conditional deletion of FOXL2 and SMAD4 in gonadotropes of adult mice causes isolated FSH deficiency","volume":"159","author":"Li","year":"2018","journal-title":"Endocrinology."},{"issue":"1","key":"2020052516194860000_CIT0013","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1677\/jme.1.01961","article-title":"Acute regulation of murine follicle-stimulating hormone beta subunit transcription by activin A","volume":"36","author":"Lamba","year":"2006","journal-title":"J Mol Endocrinol."},{"issue":"11","key":"2020052516194860000_CIT0014","doi-asserted-by":"crossref","first-page":"5577","DOI":"10.1210\/en.2008-0220","article-title":"Activator protein-1 and smad proteins synergistically regulate human follicle-stimulating hormone beta-promoter activity","volume":"149","author":"Wang","year":"2008","journal-title":"Endocrinology."},{"issue":"4","key":"2020052516194860000_CIT0015","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1210\/en.2011-1763","article-title":"FOXL2 is involved in the synergy between activin and progestins on the follicle-stimulating hormone \u03b2-subunit promoter","volume":"153","author":"Ghochani","year":"2012","journal-title":"Endocrinology."},{"issue":"1-2","key":"2020052516194860000_CIT0016","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2004.07.018","article-title":"Pituitary cell lines and their endocrine applications","volume":"228","author":"Ooi","year":"2004","journal-title":"Mol Cell Endocrinol."},{"issue":"8","key":"2020052516194860000_CIT0017","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1016\/j.fertnstert.2010.03.034","article-title":"Mechanisms of FSH synthesis: what we know, what we don\u2019t, and why you should care","volume":"93","author":"Bernard","year":"2010","journal-title":"Fertil Steril."},{"issue":"4","key":"2020052516194860000_CIT0018","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1359\/jbmr.081208","article-title":"Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women","volume":"24","author":"Ruckle","year":"2009","journal-title":"J Bone Miner Res."},{"issue":"11","key":"2020052516194860000_CIT0019","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1002\/jcph.160","article-title":"Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women","volume":"53","author":"Sherman","year":"2013","journal-title":"J Clin Pharmacol."},{"issue":"1","key":"2020052516194860000_CIT0020","first-page":"81","article-title":"Gonadotrope-specific expression of the human follicle-stimulating hormone beta-subunit gene in pituitaries of transgenic mice","volume":"6","author":"Kumar","year":"1992","journal-title":"Mol Endocrinol."},{"issue":"7","key":"2020052516194860000_CIT0021","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1210\/endo.139.7.6111","article-title":"Genetic rescue of follicle-stimulating hormone beta-deficient mice","volume":"139","author":"Kumar","year":"1998","journal-title":"Endocrinology."},{"issue":"15","key":"2020052516194860000_CIT0022","doi-asserted-by":"crossref","first-page":"5735","DOI":"10.1073\/pnas.1321404111","article-title":"Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice","volume":"111","author":"Wang","year":"2014","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"1","key":"2020052516194860000_CIT0023","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s11248-007-9134-7","article-title":"Rapid zygosity determination in mice by SYBR Green real-time genomic PCR of a crude DNA solution","volume":"17","author":"Sakurai","year":"2008","journal-title":"Transgenic Res."},{"issue":"12","key":"2020052516194860000_CIT0024","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1210\/en.2018-00770","article-title":"Betaglycan (TGFBR3) functions as an inhibin A, but not inhibin B, coreceptor in pituitary gonadotrope cells in mice","volume":"159","author":"Li","year":"2018","journal-title":"Endocrinology."},{"issue":"7","key":"2020052516194860000_CIT0025","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1210\/en.2010-0071","article-title":"Bone morphogenetic protein 2 acts via inhibitor of DNA binding proteins to synergistically regulate follicle-stimulating hormone beta transcription with activin A","volume":"151","author":"Ho","year":"2010","journal-title":"Endocrinology."},{"issue":"12","key":"2020052516194860000_CIT0026","doi-asserted-by":"crossref","first-page":"3910","DOI":"10.1210\/en.2018-00750","article-title":"Single-Cell RNA sequencing reveals novel markers of male pituitary stem cells and hormone-producing cell types","volume":"159","author":"Cheung","year":"2018","journal-title":"Endocrinology."},{"key":"2020052516194860000_CIT0027","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3389\/fendo.2019.00623","article-title":"Cell Type- and sex-dependent transcriptome profiles of rat anterior pituitary cells","volume":"10","author":"Fletcher","year":"2019","journal-title":"Front Endocrinol (Lausanne)."},{"issue":"1-2","key":"2020052516194860000_CIT0028","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.mce.2005.12.006","article-title":"Gonadotroph-specific expression of the human follicle stimulating hormone beta gene in transgenic mice","volume":"247","author":"Kumar","year":"2006","journal-title":"Mol Cell Endocrinol."},{"issue":"7","key":"2020052516194860000_CIT0029","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1210\/me.2010-0480","article-title":"SMADs and FOXL2 synergistically regulate murine FSHbeta transcription via a conserved proximal promoter element","volume":"25","author":"Tran","year":"2011","journal-title":"Mol Endocrinol."},{"issue":"5","key":"2020052516194860000_CIT0030","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1210\/me.2009-0425","article-title":"FoxL2 Is required for activin induction of the mouse and human follicle-stimulating hormone beta-subunit genes","volume":"24","author":"Corpuz","year":"2010","journal-title":"Mol Endocrinol."},{"issue":"11","key":"2020052516194860000_CIT0031","doi-asserted-by":"crossref","first-page":"5456","DOI":"10.1210\/en.2010-0605","article-title":"Activin A regulates porcine follicle-stimulating hormone beta-subunit transcription via cooperative actions of SMADs and FOXL2","volume":"151","author":"Lamba","year":"2010","journal-title":"Endocrinology."},{"issue":"2","key":"2020052516194860000_CIT0032","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/biolre\/ioz100","article-title":"Differentially expressed lncRNA-m433s1 regulates FSH secretion by functioning as a miRNA sponge in male rat anterior pituitary cells","volume":"101","author":"Han","year":"2019","journal-title":"Biol Reprod."},{"issue":"22","key":"2020052516194860000_CIT0033","doi-asserted-by":"crossref","first-page":"36553","DOI":"10.18632\/oncotarget.16615","article-title":"Roles of differential expression of microRNA-21-3p and microRNA-433 in FSH regulation in rat anterior pituitary cells","volume":"8","author":"Han","year":"2017","journal-title":"Oncotarget."},{"issue":"3","key":"2020052516194860000_CIT0034","doi-asserted-by":"crossref","first-page":"e0194300","DOI":"10.1371\/journal.pone.0194300","article-title":"Regulation of FSH expression by differentially expressed miR-186-5p in rat anterior adenohypophyseal cells","volume":"13","author":"Han","year":"2018","journal-title":"Plos One."},{"issue":"5","key":"2020052516194860000_CIT0035","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1074\/jbc.M114.621565","article-title":"Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertility defects","volume":"290","author":"Wang","year":"2015","journal-title":"J Biol Chem."},{"issue":"12","key":"2020052516194860000_CIT0036","doi-asserted-by":"crossref","DOI":"10.3390\/ijms17121987","article-title":"Tools for sequence-based miRNA target prediction: what to choose?","volume":"17","author":"Riffo-Campos","year":"2016","journal-title":"Int J Mol Sci"},{"issue":"4","key":"2020052516194860000_CIT0037","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1210\/jc.2002-021516","article-title":"Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition","volume":"88","author":"Welt","year":"2003","journal-title":"J Clin Endocrinol Metab."},{"issue":"8","key":"2020052516194860000_CIT0038","first-page":"2645","article-title":"Frequency modulation of follicle-stimulating hormone (FSH) during the luteal-follicular transition: evidence for FSH control of inhibin B in normal women","volume":"82","author":"Welt","year":"1997","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2020052516194860000_CIT0039","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1210\/endo-91-4-910","article-title":"Alterations in serum FSH-LH ratios in relation to the estrous cycle, pseudopregnancy, and gonadectomy in the mouse","volume":"91","author":"Kovacic","year":"1972","journal-title":"Endocrinology."},{"issue":"2","key":"2020052516194860000_CIT0040","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1530\/jrf.0.0320221","article-title":"Plasma LH and FSH during different oestrous cycle conditions in mice","volume":"32","author":"Murr","year":"1973","journal-title":"J Reprod Fertil."},{"issue":"7","key":"2020052516194860000_CIT0041","first-page":"898","article-title":"Gonadal steroid hormone regulation of human and mouse follicle stimulating hormone beta-subunit gene expression in vivo","volume":"7","author":"Kumar","year":"1993","journal-title":"Mol Endocrinol."},{"key":"2020052516194860000_CIT0042","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fendo.2019.00028","article-title":"Gain-of-function genetic models to study FSH action","volume":"10","author":"McDonald","year":"2019","journal-title":"Front Endocrinol (Lausanne)."}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqaa045\/32904298\/bqaa045.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/161\/5\/bqaa045\/33294159\/bqaa045.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/161\/5\/bqaa045\/33294159\/bqaa045.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T03:14:42Z","timestamp":1614914082000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqaa045\/5805118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,12]]},"references-count":42,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqaa045","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,5]]},"published":{"date-parts":[[2020,3,12]]},"article-number":"bqaa045"}}