{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:48:46Z","timestamp":1787021326628,"version":"build-2736575974"},"reference-count":52,"publisher":"The Company of Biologists","issue":"6","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"crossref","award":["18H05547"],"award-info":[{"award-number":["18H05547"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>In mammals, primordial follicles assembled in fetuses or during infancy constitute the oocyte resources for life. Exposure to 17beta-estradiol and phytogenic or endocrine-disrupting chemicals during pregnancy and\/or the perinatal period leads to the failure of normal follicle formation. However, the mechanisms underlying estrogen-mediated abnormal follicle formation and physiological follicle formation in the presence of endogenous natural estrogen are not well understood. Here, we reveal that estrogen receptor 1, activated by estrogen, binds to the 5\u2032 region of the anti-Mullerian hormone (Amh) gene and upregulates its transcription before follicle formation in cultured mouse fetal ovaries. Ectopic expression of AMH protein was observed in pregranulosa cells of these explants. Furthermore, the addition of AMH to the culture medium inhibited normal follicle formation. Conversely, alpha-fetoprotein (AFP) produced in the fetal liver reportedly blocks estrogen action, although its role in follicle formation is unclear. We further demonstrated that the addition of AFP to the medium inhibited ectopic AMH expression via estrogen, leading to successful follicle formation in vitro. Collectively, our in vitro experiments suggest that upon estrogen exposure, the integrity of follicle assembly in vivo is ensured by AFP.<\/jats:p>","DOI":"10.1242\/dev.197459","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T13:56:55Z","timestamp":1614779815000},"source":"Crossref","is-referenced-by-count":15,"title":["Blocking estrogen-induced AMH expression is crucial for normal follicle formation"],"prefix":"10.1242","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5568-6044","authenticated-orcid":false,"given":"Ren","family":"Tanimoto","sequence":"first","affiliation":[{"name":"Department of Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyono","family":"Sekii","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Morohaku","sequence":"additional","affiliation":[{"name":"Department of Agriculture and Life Sciences, Shinshu University 8304 Minami-Minowa-mura Kamiina-gun, Nagano 399-4598, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"P\u00e9pin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7445-7650","authenticated-orcid":false,"given":"Yayoi","family":"Obata","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"2021042701194706200_DEV197459C1","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1210\/endo.138.4.5042","article-title":"Isolation of a new mouse 3\u03b2-Hydroxysteroid dehydrogenase isoform, 3\u03b2-HSD VI, expressed during early pregnancy","volume":"138","author":"Abbaszade","year":"1997","journal-title":"Endocrinology"},{"key":"2021042701194706200_DEV197459C2","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1292\/jvms1939.38.339","article-title":"The \u03b1-fetoprotein level in the sera of bovine fetuses and calves","volume":"38","author":"Abe","year":"1976","journal-title":"Japanese J. Vet. Sci."},{"key":"2021042701194706200_DEV197459C3","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/nn1624","article-title":"Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens","volume":"9","author":"Bakker","year":"2006","journal-title":"Nat. Neurosci."},{"key":"2021042701194706200_DEV197459C4","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/0960-0760(93)90209-F","article-title":"Placental 17\u03b2-hydroxysteroid oxidoreductase, lactate dehydrogenase and malate dehydrogenase during the latter half of pregnancy in the mouse","volume":"46","author":"Blomquist","year":"1993","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"2021042701194706200_DEV197459C5","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/0014-4827(61)90449-9","article-title":"Oogenesis in the mouse: a study of the meiotic prophase","volume":"24","author":"Borum","year":"1961","journal-title":"Exp. Cell Res."},{"key":"2021042701194706200_DEV197459C6","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ydbio.2006.06.025","article-title":"Postnatal regulation of germ cells by activin: the establishment of the initial follicle pool","volume":"298","author":"Bristol-Gould","year":"2006","journal-title":"Dev. Biol."},{"key":"2021042701194706200_DEV197459C7","doi-asserted-by":"publisher","first-page":"3580","DOI":"10.1210\/en.2007-0088","article-title":"Estradiol, progesterone, and genistein inhibit oocyte nest breakdown and primordial follicle assembly in the neonatal mouse ovary in vitro and in vivo","volume":"148","author":"Chen","year":"2007","journal-title":"Endocrinology"},{"key":"2021042701194706200_DEV197459C8","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1677\/JOE-09-0109","article-title":"Estrogen can signal through multiple pathways to regulate oocyte cyst breakdown and primordial follicle assembly in the neonatal mouse ovary","volume":"202","author":"Chen","year":"2009","journal-title":"J. Endocrinol."},{"key":"2021042701194706200_DEV197459C9","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.1210\/endo.140.12.7204","article-title":"Control of primordial follicle recruitment by anti-m\u00fcllerian hormone in the mouse ovary","volume":"140","author":"Durlinger","year":"1999","journal-title":"Endocrinology"},{"key":"2021042701194706200_DEV197459C10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1095\/biolreprod.114.119214","article-title":"The steroid hormone environment during primordial follicle formation in perinatal mouse ovaries","volume":"91","author":"Dutta","year":"2014","journal-title":"Biol. Reprod."},{"key":"2021042701194706200_DEV197459C11","doi-asserted-by":"publisher","first-page":"12865","DOI":"10.1073\/pnas.202215399","article-title":"Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility","volume":"99","author":"Gabant","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042701194706200_DEV197459C53","doi-asserted-by":"publisher","author":"Guerrier","year":"1990","DOI":"10.1530\/jrf.0.0880695"},{"key":"2021042701194706200_DEV197459C12","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.jsbmb.2008.03.027","article-title":"Estetrol: a unique steroid in human pregnancy","volume":"110","author":"Holinka","year":"2008","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"2021042701194706200_DEV197459C13","doi-asserted-by":"publisher","first-page":"17525","DOI":"10.1073\/pnas.1207854109","article-title":"Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey","volume":"109","author":"Hunt","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042701194706200_DEV197459C14","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1002\/tera.1420340105","article-title":"Frequent occurrence of polyovular follicles in ovaries of mice exposed neonatally to diethylstibestrol","volume":"34","author":"Iguchi","year":"1986","journal-title":"Teratology"},{"key":"2021042701194706200_DEV197459C15","first-page":"415","article-title":"Inhibition of estrogen-dependent breast cancer growth by a reaction product of alpha-fetoprotein and estradiol","volume":"50","author":"Jacobson","year":"1990","journal-title":"Cancer Res."},{"key":"2021042701194706200_DEV197459C16","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1095\/biolreprod67.4.1285","article-title":"Neonatal exposure to genistein induces estrogen receptor (ER)\u03b1 expression and multioocyte follicles in the maturing mouse ovary: evidence for ER\u03b2-mediated and nonestrogenic actions","volume":"67","author":"Jefferson","year":"2002","journal-title":"Biol. Reprod."},{"key":"2021042701194706200_DEV197459C17","doi-asserted-by":"publisher","first-page":"E1688","DOI":"10.1073\/pnas.1620729114","article-title":"AMH\/MIS as a contraceptive that protects the ovarian reserve during chemotherapy","volume":"114","author":"Kano","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042701194706200_DEV197459C18","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1210\/en.2010-0950","article-title":"Follistatin regulates germ cell nest breakdown and primordial follicle formation","volume":"152","author":"Kimura","year":"2011","journal-title":"Endocrinology"},{"key":"2021042701194706200_DEV197459C19","doi-asserted-by":"publisher","first-page":"2905","DOI":"10.1093\/nar\/29.14.2905","article-title":"Estrogen receptor interaction with estrogen response elements","volume":"29","author":"Klinge","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2021042701194706200_DEV197459C20","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1038\/nrg1225","article-title":"Developmental genetics of the female reproductive tract in mammals","volume":"4","author":"Kobayashi","year":"2003","journal-title":"Nat. Rev. Genet."},{"key":"2021042701194706200_DEV197459C21","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/978-1-4939-3127-9_7","article-title":"Chromatin immunoprecipitation with estrogen receptor 1 and the promoter of Greb1 in TM4 sertoli cells","volume-title":"Estrogen Receptors. Methods in Molecular Biology","author":"Lin","year":"2016"},{"key":"2021042701194706200_DEV197459C22","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1152\/physrev.00010.2007","article-title":"Estradiol and the developing brain","volume":"88","author":"McCarthy","year":"2008","journal-title":"Physiol. Rev."},{"key":"2021042701194706200_DEV197459C23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1098\/rstb.1988.0109","article-title":"Somatic and germ-cell sex in mammals","volume":"322","author":"McLaren","year":"1988","journal-title":"Philos. Trans. R. Soc. Lond. B. Biol. Sci."},{"key":"2021042701194706200_DEV197459C24","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1210\/edrv-10-3-232","article-title":"The free hormone hypothesis: a physiologically based mathematical model","volume":"10","author":"Mendel","year":"1989","journal-title":"Endocr. Rev."},{"key":"2021042701194706200_DEV197459C25","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1097\/01.OGX.0000099770.97668.18","article-title":"Levels of alpha-fetoprotein during pregnancy and early infancy in normal and disease states","volume":"58","author":"Mizejewski","year":"2003","journal-title":"Obstet. Gynecol. Surv."},{"key":"2021042701194706200_DEV197459C26","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1262\/jrd.2019-024","article-title":"A way for in vitro\/ex vivo egg production in mammals","volume":"65","author":"Morohaku","year":"2019","journal-title":"J. Reprod. Dev."},{"key":"2021042701194706200_DEV197459C27","doi-asserted-by":"publisher","first-page":"9021","DOI":"10.1073\/pnas.1603817113","article-title":"Complete in vitro generation of fertile oocytes from mouse primordial germ cells","volume":"113","author":"Morohaku","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042701194706200_DEV197459C28","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1007\/s10439-017-1815-7","article-title":"Differentiation of mouse primordial germ cells into functional oocytes in vitro","volume":"45","author":"Morohaku","year":"2017","journal-title":"Ann. Biomed. Eng."},{"key":"2021042701194706200_DEV197459C29","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1038\/nprot.2017.069","article-title":"Development of fertile mouse oocytes from mitotic germ cells in vitro","volume":"12","author":"Morohaku","year":"2017","journal-title":"Nat. Protoc."},{"key":"2021042701194706200_DEV197459C31","first-page":"359","article-title":"The dynamics of \u03b1 fetoprotein and albumin synthesis in human and rat liver during normal ontogeny","volume":"86","author":"Nayak","year":"1977","journal-title":"Am. J. Pathol."},{"key":"2021042701194706200_DEV197459C32","doi-asserted-by":"publisher","first-page":"e20087","DOI":"10.1371\/journal.pone.0020087","article-title":"Inhibitory actions of Anti-M\u00fcllerian Hormone (AMH) on ovarian primordial follicle assembly","volume":"6","author":"Nilsson","year":"2011","journal-title":"PLoS ONE"},{"key":"2021042701194706200_DEV197459C33","doi-asserted-by":"publisher","first-page":"3102","DOI":"10.1073\/pnas.88.8.3102","article-title":"Localization of the estrogen-binding site of alpha-fetoprotein in the chimeric human-rat proteins","volume":"88","author":"Nishi","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042701194706200_DEV197459C34","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1084\/jem.145.4.819","article-title":"Genetic control of alpha-fetoprotein synthesis in the mouse","volume":"145","author":"Olsson","year":"1977","journal-title":"J. Exp. Med."},{"key":"2021042701194706200_DEV197459C35","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.ydbio.2005.08.023","article-title":"Transcript profiling during mouse oocyte development and the effect of gonadotropin priming and development in vitro","volume":"286","author":"Pan","year":"2005","journal-title":"Dev. Biol."},{"key":"2021042701194706200_DEV197459C36","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1530\/REP-11-0299","article-title":"Follicular assembly: mechanisms of action","volume":"143","author":"Pepling","year":"2012","journal-title":"Reproduction"},{"key":"2021042701194706200_DEV197459C37","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1006\/dbio.2001.0269","article-title":"Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles","volume":"234","author":"Pepling","year":"2001","journal-title":"Dev. Biol."},{"key":"2021042701194706200_DEV197459C38","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.jsbmb.2010.12.012","article-title":"Assisted reproduction technologies alter steroid delivery to the mouse fetus during pregnancy","volume":"126","author":"Raunig","year":"2011","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"2021042701194706200_DEV197459C39","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.tiv.2014.09.008","article-title":"Validation of murine and human placental explant cultures for use in sex steroid and phase II conjugation toxicology studies","volume":"29","author":"Sato","year":"2015","journal-title":"Toxicol. Vitr."},{"key":"2021042701194706200_DEV197459C40","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/s41591-018-0035-5","article-title":"Elevated prenatal anti-M\u00fcllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood","volume":"24","author":"Tata","year":"2018","journal-title":"Nat. Med."},{"key":"2021042701194706200_DEV197459C41","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/0022-4731(84)90078-5","article-title":"Augmentation of aromatase activity by FSH in ovaries of fetal and neonatal mice in organ culture","volume":"20","author":"Terada","year":"1984","journal-title":"J. Steroid Biochem."},{"key":"2021042701194706200_DEV197459C42","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1210\/en.2008-0213","article-title":"Suppression of notch signaling in the neonatal mouse ovary decreases primordial follicle formation","volume":"150","author":"Trombly","year":"2009","journal-title":"Endocrinology"},{"key":"2021042701194706200_DEV197459C43","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1093\/hmg\/ddh124","article-title":"Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development","volume":"13","author":"Uda","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2021042701194706200_DEV197459C44","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1073\/pnas.73.5.1452","article-title":"Alpha-fetoprotein: the major high-affinity estrogen binder in rat uterine cytosols","volume":"73","author":"Uriel","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042701194706200_DEV197459C45","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1210\/me.2013-1288","article-title":"Notch signaling regulates ovarian follicle formation and coordinates follicular growth","volume":"28","author":"Vanorny","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"2021042701194706200_DEV197459C46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1186\/s13059-015-0769-z","article-title":"Deep sequencing and de novo assembly of the mouse oocyte transcriptome define the contribution of transcription to the DNA methylation landscape","volume":"16","author":"Veselovska","year":"2015","journal-title":"Genome Biol."},{"key":"2021042701194706200_DEV197459C47","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1210\/en.2006-1193","article-title":"Development of primordial follicles in the hamster: role of Estradiol-17\u03b2","volume":"148","author":"Wang","year":"2007","journal-title":"Endocrinology"},{"key":"2021042701194706200_DEV197459C48","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1007\/s00018-017-2480-6","article-title":"Mechanisms controlling germline cyst breakdown and primordial follicle formation","volume":"74","author":"Wang","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"2021042701194706200_DEV197459C49","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1051\/rnd:19930205","article-title":"Estrogen production by fetal and infantile rat ovaries","volume":"33","author":"Weniger","year":"1993","journal-title":"Reprod. Nutr. Dev."},{"key":"2021042701194706200_DEV197459C50","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1741-7007-11-13","article-title":"Notch2 is required in somatic cells for breakdown of ovarian germ-cell nests and formation of primordial follicles","volume":"11","author":"Xu","year":"2013","journal-title":"BMC Biol."},{"key":"2021042701194706200_DEV197459C51","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1095\/biolreprod.107.066688","article-title":"The capacity of primordial follicles in fetal bovine ovaries to initiate growth in vitro develops during mid-gestation and is associated with meiotic arrest of oocytes1","volume":"78","author":"Yang","year":"2008","journal-title":"Biol. Reprod."},{"key":"2021042701194706200_DEV197459C52","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1095\/biolreprod67.4.1148","article-title":"Developmental regulation of baboon fetal ovarian maturation by Estrogen1","volume":"67","author":"Zachos","year":"2002","journal-title":"Biol. Reprod."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.197459","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.197459\/1818416\/dev197459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.197459\/1818416\/dev197459.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T22:53:50Z","timestamp":1619477630000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/148\/6\/dev197459\/237850\/Blocking-estrogen-induced-AMH-expression-is"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,15]]},"references-count":52,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,3,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.197459","relation":{},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,15]]},"article-number":"dev197459"}}