{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:38:48Z","timestamp":1790800728762,"version":"4.1.0"},"reference-count":41,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"name":"the Major Research Plan","award":["2013CB945001"],"award-info":[{"award-number":["2013CB945001"]}]},{"name":"the National Science Fund for Distinguished Young Scholars","award":["81525011"],"award-info":[{"award-number":["81525011"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31471348"],"award-info":[{"award-number":["31471348"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31671496"],"award-info":[{"award-number":["31671496"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National key R&D program of China","award":["2016YFA0500901"],"award-info":[{"award-number":["2016YFA0500901"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Supporting cells (Sertoli and granulosa) and steroidogenic cells (Leydig and theca-interstitium) are two major somatic cell types in mammalian gonads. However, the mechanisms that control their differentiation during gonad development remain elusive. In this study, we found deletion of Wt1 in ovary after sex determination caused ectopic development of steroidogenic cells at embryonic stage. Furthermore, the differentiation of both Sertoli and granulosa cells was blocked when Wt1 was deleted before sex determination and most genital ridge somatic cells differentiated into steroidogenic cells in both male and female gonads. Further studies revealed WT1 repressed Sf1 expression by directly binding to the Sf1 promoter region, and the repressive function was completely abolished when WT1 binding sites were mutated. This study demonstrated Wt1 is required for the lineage specification of both Sertoli and granulosa cells by repressing Sf1 expression. Without Wt1, the expression of Sf1 was upregulated and the somatic cells differentiated into steroidogenic cells instead of supporting cells. Our study uncovered a novel mechanism of somatic cell differentiation during gonad development.<\/jats:p>","DOI":"10.1242\/dev.144105","type":"journal-article","created":{"date-parts":[[2016,11,26]],"date-time":"2016-11-26T01:50:16Z","timestamp":1480125016000},"source":"Crossref","is-referenced-by-count":45,"title":["<i>Wt1<\/i> directs the lineage specification of sertoli and granulosa cells by repressing <i>Sf1<\/i> expression"],"prefix":"10.1242","author":[{"given":"Min","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhong","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwen","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqiong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbo","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Qin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"name":"University of Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahua","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunsheng","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhou","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki","family":"Huff","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Texas M. D. Anderson Cancer Center; Graduate Programs in Human Molecular Genetics and Genes and Development, University of Texas, Houston, Texas, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4415-6165","authenticated-orcid":false,"given":"Fei","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2016,1,1]]},"reference":[{"key":"2021042608522235800_DEV144105C1","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/0925-4773(93)90090-K","article-title":"The expression of the Wilms\u2019 tumour gene, WT1, in the developing mammalian embryo","volume":"40","author":"Armstrong","year":"1993","journal-title":"Mech. Dev."},{"key":"2021042608522235800_DEV144105C2","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.devcel.2013.09.003","article-title":"WT1 maintains adrenal-gonadal primordium identity and marks a population of AGP-like progenitors within the adrenal gland","volume":"27","author":"Bandiera","year":"2013","journal-title":"Dev. Cell"},{"key":"2021042608522235800_DEV144105C3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.2164\/jandrol.109.008318","article-title":"Fetal Leydig cells: progenitor cell maintenance and differentiation","volume":"31","author":"Barsoum","year":"2010","journal-title":"J. Androl."},{"key":"2021042608522235800_DEV144105C4","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1093\/hmg\/ddp283","article-title":"A cell-autonomous role for WT1 in regulating Sry in vivo","volume":"18","author":"Bradford","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2021042608522235800_DEV144105C5","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/ng0592-144","article-title":"Germline intronic and exonic mutations in the Wilms\u2019 tumour gene (WT1) affecting urogenital development","volume":"1","author":"Bruening","year":"1992","journal-title":"Nat. Genet."},{"key":"2021042608522235800_DEV144105C6","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/0092-8674(90)90601-A","article-title":"Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms\u2019 tumor locus","volume":"60","author":"Call","year":"1990","journal-title":"Cell"},{"key":"2021042608522235800_DEV144105C7","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1093\/hmg\/ddn016","article-title":"Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary","volume":"17","author":"Chassot","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2021042608522235800_DEV144105C8","first-page":"6125","article-title":"Inherited WT1 mutation in Denys-Drash syndrome","volume":"52","author":"Coppes","year":"1992","journal-title":"Cancer Res."},{"key":"2021042608522235800_DEV144105C9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.ydbio.2011.01.011","article-title":"Two distinct origins for Leydig cell progenitors in the fetal testis","volume":"352","author":"DeFalco","year":"2011","journal-title":"Dev. Biol."},{"key":"2021042608522235800_DEV144105C10","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/S0022-3476(70)80409-7","article-title":"A syndrome of pseudohermaphroditism, Wilms\u2019 tumor, hypertension, and degenerative renal disease","volume":"76","author":"Drash","year":"1970","journal-title":"J. Pediatr."},{"key":"2021042608522235800_DEV144105C11","doi-asserted-by":"publisher","first-page":"11987","DOI":"10.1073\/pnas.0600994103","article-title":"The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis","volume":"103","author":"Gao","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608522235800_DEV144105C12","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1038\/343774a0","article-title":"Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping","volume":"343","author":"Gessler","year":"1990","journal-title":"Nature"},{"key":"2021042608522235800_DEV144105C13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/346245a0","article-title":"A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes","volume":"346","author":"Gubbay","year":"1990","journal-title":"Nature"},{"key":"2021042608522235800_DEV144105C14","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/S0092-8674(01)00453-6","article-title":"Two splice variants of the Wilms\u2019 tumor 1 gene have distinct functions during sex determination and nephron formation","volume":"106","author":"Hammes","year":"2001","journal-title":"Cell"},{"key":"2021042608522235800_DEV144105C15","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1172\/JCI43772","article-title":"Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1\/2 phosphorylation","volume":"121","author":"Hu","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2021042608522235800_DEV144105C16","first-page":"997","article-title":"Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT","volume":"48","author":"Huff","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"2021042608522235800_DEV144105C17","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1210\/mend.7.7.8413309","article-title":"Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression","volume":"7","author":"Ikeda","year":"1993","journal-title":"Mol. Endocrinol."},{"key":"2021042608522235800_DEV144105C18","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1210\/mend.8.5.8058073","article-title":"Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases","volume":"8","author":"Ikeda","year":"1994","journal-title":"Mol. Endocrinol."},{"key":"2021042608522235800_DEV144105C19","doi-asserted-by":"publisher","first-page":"3663","DOI":"10.1242\/dev.00591","article-title":"Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad","volume":"130","author":"Jeays-Ward","year":"2003","journal-title":"Development"},{"key":"2021042608522235800_DEV144105C20","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.ydbio.2004.08.049","article-title":"Wnt4 is required for proper male as well as female sexual development","volume":"276","author":"Jeays-Ward","year":"2004","journal-title":"Dev. Biol."},{"key":"2021042608522235800_DEV144105C21","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/351117a0","article-title":"Male development of chromosomally female mice transgenic for Sry","volume":"351","author":"Koopman","year":"1991","journal-title":"Nature"},{"key":"2021042608522235800_DEV144105C22","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/0092-8674(93)90515-R","article-title":"WT-1 is required for early kidney development","volume":"74","author":"Kreidberg","year":"1993","journal-title":"Cell"},{"key":"2021042608522235800_DEV144105C23","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1095\/biolreprod.113.109405","article-title":"The heat-induced reversible change in the Blood-Testis Barrier (BTB) is regulated by the Androgen Receptor (AR) via the Partitioning-Defective Protein (Par) polarity complex in the mouse","volume":"89","author":"Li","year":"2013","journal-title":"Biol. Reprod."},{"key":"2021042608522235800_DEV144105C24","doi-asserted-by":"publisher","first-page":"6934","DOI":"10.1038\/ncomms7934","article-title":"Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells","volume":"6","author":"Liu","year":"2015","journal-title":"Nat. Commun."},{"key":"2021042608522235800_DEV144105C25","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/0092-8674(94)90211-9","article-title":"A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation","volume":"77","author":"Luo","year":"1994","journal-title":"Cell"},{"key":"2021042608522235800_DEV144105C26","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1210\/mend.7.9.8247022","article-title":"Activation of CYP11A and CYP11B gene promoters by the steroidogenic cell-specific transcription factor, Ad4BP","volume":"7","author":"Morohashi","year":"1993","journal-title":"Mol. Endocrinol."},{"key":"2021042608522235800_DEV144105C27","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/353431a0","article-title":"WT1 mutations contribute to abnormal genital system development and hereditary Wilms\u2019 tumour","volume":"353","author":"Pelletier","year":"1991","journal-title":"Nature"},{"key":"2021042608522235800_DEV144105C28","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1101\/gad.5.8.1345","article-title":"Expression of the Wilms\u2019 tumor gene WT1 in the murine urogenital system","volume":"5","author":"Pelletier","year":"1991","journal-title":"Genes Dev."},{"key":"2021042608522235800_DEV144105C29","doi-asserted-by":"publisher","first-page":"10939","DOI":"10.1073\/pnas.92.24.10939","article-title":"Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids","volume":"92","author":"Sadovsky","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608522235800_DEV144105C30","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/346240a0","article-title":"A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif","volume":"346","author":"Sinclair","year":"1990","journal-title":"Nature"},{"key":"2021042608522235800_DEV144105C31","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1096\/fj.13-246108","article-title":"FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice","volume":"28","author":"Takasawa","year":"2014","journal-title":"FASEB J."},{"key":"2021042608522235800_DEV144105C32","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/17068","article-title":"Female development in mammals is regulated by Wnt-4 signalling","volume":"397","author":"Vainio","year":"1999","journal-title":"Nature"},{"key":"2021042608522235800_DEV144105C33","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1242\/dev.004390","article-title":"Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage","volume":"134","author":"Val","year":"2007","journal-title":"Development"},{"key":"2021042608522235800_DEV144105C34","doi-asserted-by":"publisher","first-page":"e1003645","DOI":"10.1371\/journal.pgen.1003645","article-title":"The Wilms tumor gene, Wt1, is critical for mouse spermatogenesis via regulation of sertoli cell polarity and is associated with non-obstructive azoospermia in humans","volume":"9","author":"Wang","year":"2013","journal-title":"PLoS Genet."},{"key":"2021042608522235800_DEV144105C35","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.envres.2008.09.005","article-title":"Longitudinal associations between lead dose and renal function in lead workers","volume":"109","author":"Weaver","year":"2009","journal-title":"Environ. Res."},{"key":"2021042608522235800_DEV144105C36","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1101\/gad.220102","article-title":"The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1","volume":"16","author":"Wilhelm","year":"2002","journal-title":"Genes Dev."},{"key":"2021042608522235800_DEV144105C37","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1210\/mend.11.2.9881","article-title":"Characterization of the promoter of SF-1, an orphan nuclear receptor required for adrenal and gonadal development","volume":"11","author":"Woodson","year":"1997","journal-title":"Mol. Endocrinol."},{"key":"2021042608522235800_DEV144105C38","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1002\/dvdy.20042","article-title":"Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis","volume":"230","author":"Yao","year":"2004","journal-title":"Dev. Dyn."},{"key":"2021042608522235800_DEV144105C39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1242\/dev.124.1.101","article-title":"Emx1 and Emx2 functions in development of dorsal telencephalon","volume":"124","author":"Yoshida","year":"1997","journal-title":"Development"},{"key":"2021042608522235800_DEV144105C40","doi-asserted-by":"publisher","first-page":"4003","DOI":"10.1073\/pnas.1422371112","article-title":"Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation","volume":"112","author":"Zhang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608522235800_DEV144105C41","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nature07060","article-title":"Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart","volume":"454","author":"Zhou","year":"2008","journal-title":"Nature"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.144105","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/144\/1\/44\/1846877\/dev144105.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.144105\/2053302\/dev_144105v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.144105\/2053302\/dev_144105v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T17:00:58Z","timestamp":1621357258000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.144105\/264302\/Wt1-directs-the-lineage-specification-of-sertoli"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":41,"URL":"https:\/\/doi.org\/10.1242\/dev.144105","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2016,1,1]]},"article-number":"dev.144105"}}