{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T03:16:16Z","timestamp":1774408576102,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T00:00:00Z","timestamp":1573603200000},"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":["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":["2015-05178"],"award-info":[{"award-number":["2015-05178"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Activins selectively stimulate follicle-stimulating hormone (FSH) secretion by pituitary gonadotrope cells. More recently, other members of the TGFbeta superfamily, the bone morphogenetic proteins (BMPs), were reported to regulate FSH synthesis. Activins and BMPs independently and synergistically stimulate transcription of the FSHbeta subunit (Fshb) gene in immortalized gonadotrope-like cells. Both ligands can signal via the activin receptor type IIA (ACVR2A) to regulate FSH synthesis in vitro. In vivo, global Acvr2a knockout mice exhibit a 60% reduction in circulating FSH relative to wild-type animals, suggesting that activins, BMPs, or related ligands might signal through additional type II receptors to regulate FSH in vivo. Although the leading candidates are ACVR2B and the BMP type II receptor (BMPR2), only the latter mediates activin or BMP2 induction of Fshb transcription in vitro. Here, we generated mice carrying a loss of function mutation in Bmpr2 specifically in gonadotropes. Puberty onset, estrous cyclicity, and reproductive organ weights were similar between control and conditional knockout females. Serum FSH and luteinizing hormone (LH) and pituitary expression of Fshb and the LHbeta subunit (Lhb) were similarly unaffected by the gene deletion in both sexes. These results suggest that BMPR2 might not play a necessary role in FSH synthesis or secretion in vivo or that another type II receptor, such as ACVR2A, can fully compensate for its absence. These data also further contribute to the emerging concept that BMPs may not be physiological regulators of FSH in vivo.<\/jats:p>","DOI":"10.1093\/biolre\/ioz206","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:48:42Z","timestamp":1573692522000},"page":"639-646","source":"Crossref","is-referenced-by-count":10,"title":["Gonadotrope-specific deletion of the BMP type 2 receptor does not affect reproductive physiology in mice\u2020\u2021"],"prefix":"10.1093","volume":"102","author":[{"given":"Luisina","family":"Ongaro","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics"},{"name":"Centre for Research in Reproduction and Development, McGill University, Montreal, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics"},{"name":"Centre for Research in Reproduction and Development, McGill University, Montreal, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiming","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics"},{"name":"Centre for Research in Reproduction and Development, McGill University, Montreal, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Boehm","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Saarland University School of Medicine, Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J","family":"Bernard","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics"},{"name":"Centre for Research in Reproduction and Development, McGill University, Montreal, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,11,13]]},"reference":[{"key":"2020031302272334800_ref1","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/374354a0","article-title":"Functional analysis of activins during mammalian development","volume":"374","author":"Matzuk","year":"1995","journal-title":"Nature"},{"key":"2020031302272334800_ref2","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/0092-8674(92)90395-S","article-title":"Beta signals through a heteromeric protein kinase receptor complex","volume":"71","author":"Wrana","year":"1992","journal-title":"Cell"},{"key":"2020031302272334800_ref3","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/321779a0","article-title":"Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin","volume":"321","author":"Ling","year":"1986","journal-title":"Nature"},{"key":"2020031302272334800_ref4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1677\/jme.1.02196","article-title":"Bone morphogenetic protein 2 and activin a synergistically stimulate follicle-stimulating hormone beta subunit transcription","volume":"38","author":"Lee","year":"2007","journal-title":"J Mol Endocrinol"},{"key":"2020031302272334800_ref5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.mce.2011.08.001","article-title":"Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LbetaT2 gonadotrope cells","volume":"348","author":"Takeda","year":"2012","journal-title":"Mol Cell Endocrinol"},{"key":"2020031302272334800_ref6","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1210\/endo.142.6.8159","article-title":"A novel role for bone morphogenetic proteins in the synthesis of follicle-stimulating hormone","volume":"142","author":"Huang","year":"2001","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1677\/JOE-07-0542","article-title":"Bone morphogenetic protein-4 interacts with activin and GnRH to modulate gonadotrophin secretion in LbetaT2 gonadotrophs","volume":"196","author":"Nicol","year":"2008","journal-title":"J Endocrinol"},{"key":"2020031302272334800_ref8","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1016\/j.cellsig.2013.09.002","article-title":"Activins bind and signal via bone morphogenetic protein receptor type II (BMPR2) in immortalized gonadotrope-like cells","volume":"25","author":"Rejon","year":"2013","journal-title":"Cell Signal"},{"key":"2020031302272334800_ref9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12964-015-0104-z","article-title":"Activin a inhibits BMP-signaling by binding ACVR2A and ACVR2B","volume":"13","author":"Olsen","year":"2015","journal-title":"Cell Commun Signal"},{"key":"2020031302272334800_ref10","first-page":"367","article-title":"Formation and activation by phosphorylation of activin receptor complexes","volume":"10","author":"Willis","year":"1996","journal-title":"Mol Endocrinol"},{"key":"2020031302272334800_ref11","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1083\/jcb.130.1.217","article-title":"Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects","volume":"130","author":"Yamashita","year":"1995","journal-title":"J Cell Biol"},{"key":"2020031302272334800_ref12","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/0092-8674(93)90488-C","article-title":"Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors","volume":"75","author":"Attisano","year":"1993","journal-title":"Cell"},{"key":"2020031302272334800_ref13","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.1073\/pnas.92.17.7632","article-title":"Cloning and characterization of a human type II receptor for bone morphogenetic proteins","volume":"92","author":"Rosenzweig","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020031302272334800_ref14","doi-asserted-by":"crossref","first-page":"10792","DOI":"10.1074\/jbc.M115.713487","article-title":"Transforming growth factor-beta family ligands can function as antagonists by competing for type II receptor binding","volume":"291","author":"Aykul","year":"2016","journal-title":"J Biol Chem"},{"key":"2020031302272334800_ref15","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"},{"key":"2020031302272334800_ref16","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.mce.2004.03.009","article-title":"Activin isoforms signal through type I receptor serine\/threonine kinase ALK7","volume":"220","author":"Tsuchida","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"2020031302272334800_ref17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1126\/science.8140412","article-title":"Characterization of type I receptors for transforming growth factor-beta and activin","volume":"264","author":"ten Dijke","year":"1994","journal-title":"Science"},{"key":"2020031302272334800_ref18","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1530\/JOE-16-0053","article-title":"Normal gonadotropin production and fertility in gonadotrope-specific Bmpr1a knockout mice","volume":"229","author":"Zhou","year":"2016","journal-title":"J Endocrinol"},{"key":"2020031302272334800_ref19","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1210\/en.2018-01038","article-title":"TGF-beta superfamily regulation of follicle-stimulating hormone synthesis by Gonadotrope cells: Is there a role for bone morphogenetic proteins?","volume":"160","author":"Ongaro","year":"2019","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref20","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"},{"key":"2020031302272334800_ref21","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0092-8674(92)90209-U","article-title":"Novel activin receptors: Distinct genes and alternative mRNA splicing generate a repertoire of serine\/threonine kinase receptors","volume":"68","author":"Attisano","year":"1992","journal-title":"Cell"},{"key":"2020031302272334800_ref22","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1128\/MCB.01595-12","article-title":"Constitutively active ALK2 receptor mutants require type II receptor cooperation","volume":"33","author":"Bagarova","year":"2013","journal-title":"Mol Cell Biol"},{"key":"2020031302272334800_ref23","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.cellsig.2013.03.002","article-title":"Cycloheximide inhibits follicle-stimulating hormone beta subunit transcription by blocking de novo synthesis of the labile activin type II receptor in gonadotrope cells","volume":"25","author":"Rejon","year":"2013","journal-title":"Cell Signal"},{"key":"2020031302272334800_ref24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1006\/dbio.2000.9670","article-title":"BMP type II receptor is required for gastrulation and early development of mouse embryos","volume":"221","author":"Beppu","year":"2000","journal-title":"Dev Biol"},{"key":"2020031302272334800_ref25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/gene.20099","article-title":"Generation of a floxed allele of the mouse BMP type II receptor gene","volume":"41","author":"Beppu","year":"2005","journal-title":"Genesis"},{"key":"2020031302272334800_ref26","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1210\/en.2007-1502","article-title":"Functional characterization of genetically labeled gonadotropes","volume":"149","author":"Wen","year":"2008","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref27","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"2020031302272334800_ref28","doi-asserted-by":"crossref","DOI":"10.1002\/0471142301.nsa04is48","article-title":"Assessing reproductive status\/stages in mice","author":"Caligioni","year":"2009","journal-title":"Curr Protoc Neurosci"},{"key":"2020031302272334800_ref29","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(\u2212Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2020031302272334800_ref30","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0059058","article-title":"NR5A2 regulates Lhb and Fshb transcription in gonadotrope-like cells in vitro, but is dispensable for gonadotropin synthesis and fertility in vivo","volume":"8","author":"Fortin","year":"2013","journal-title":"PLoS One"},{"key":"2020031302272334800_ref31","doi-asserted-by":"crossref","first-page":"16372","DOI":"10.1073\/pnas.1000423107","article-title":"Embryonic gonadotropin-releasing hormone signaling is necessary for maturation of the male reproductive axis","volume":"107","author":"Wen","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020031302272334800_ref32","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"},{"key":"2020031302272334800_ref33","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"},{"key":"2020031302272334800_ref34","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"},{"key":"2020031302272334800_ref35","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"},{"key":"2020031302272334800_ref36","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"},{"key":"2020031302272334800_ref37","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1101\/gad.11.14.1812","article-title":"The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse","volume":"11","author":"Oh","year":"1997","journal-title":"Genes Dev"},{"key":"2020031302272334800_ref38","doi-asserted-by":"crossref","first-page":"E2353","DOI":"10.1073\/pnas.1206410109","article-title":"Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin\/activin signaling pathway","volume":"109","author":"Lee","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020031302272334800_ref39","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1095\/biolreprod.108.074211","article-title":"Bone morphogenetic protein 2 signals via BMPR1A to regulate murine follicle-stimulating hormone beta subunit transcription","volume":"81","author":"Ho","year":"2009","journal-title":"Biol Reprod"},{"key":"2020031302272334800_ref40","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1210\/en.2010-1208","article-title":"Genetic identification of GnRH receptor neurons: A new model for studying neural circuits underlying reproductive physiology in the mouse brain","volume":"152","author":"Wen","year":"2011","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref41","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1210\/en.2017-00653","article-title":"Sex- and age-specific impact of ERK loss within the pituitary Gonadotrope in mice","volume":"159","author":"Brown","year":"2018","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref42","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1210\/en.2014-1296","article-title":"Beta-catenin stabilization in gonadotropes impairs FSH synthesis in male mice in vivo","volume":"156","author":"Boerboom","year":"2015","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref43","doi-asserted-by":"crossref","DOI":"10.1210\/en.2017-00844","article-title":"GnRH receptor expression and reproductive function depend on JUN in the GnRH receptor-expressing cells","author":"Jonak","year":"2018","journal-title":"Endocrinology"},{"key":"2020031302272334800_ref44","doi-asserted-by":"crossref","first-page":"R1258","DOI":"10.1152\/ajpregu.00529.2015","article-title":"Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state","volume":"310","author":"Allen","year":"2016","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2020031302272334800_ref45","doi-asserted-by":"crossref","first-page":"24443","DOI":"10.1074\/jbc.M502825200","article-title":"Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells","volume":"280","author":"Yu","year":"2005","journal-title":"J Biol Chem"},{"key":"2020031302272334800_ref46","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1182\/blood-2014-04-572644","article-title":"BMP type II receptors have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism","volume":"124","author":"Mayeur","year":"2014","journal-title":"Blood"},{"key":"2020031302272334800_ref47","doi-asserted-by":"crossref","first-page":"13809","DOI":"10.1074\/jbc.M117.782128","article-title":"Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass","volume":"292","author":"Goh","year":"2017","journal-title":"J Biol Chem"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioz206\/30703760\/ioz206.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/biolreprod\/article-pdf\/102\/3\/639\/32900416\/ioz206.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/biolreprod\/article-pdf\/102\/3\/639\/32900416\/ioz206.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T06:27:52Z","timestamp":1584080872000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/102\/3\/639\/5625169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,13]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,11,13]]},"published-print":{"date-parts":[[2020,3,13]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioz206","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,3]]},"published":{"date-parts":[[2019,11,13]]}}}