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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2018,5,22]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Sex determination involves antagonistic interactions between the testis-determining (SRY-SOX9-FGF9) and ovary-promoting (RSPO1-WNT\/\u03b2-catenin-FOXL2) pathways, but the underlying molecular mechanisms remain unclear. We show that ZNRF3, an E3 ubiquitin ligase that inhibits WNT signaling and is a direct target of RSPO1-mediated membrane clearance, is testis-determining in mice. Testis determination defects in the absence of ZNRF3 arise due to ectopic canonical WNT signaling in XY gonads at the sex-determining stage. We identify human\n                    <jats:italic>ZNRF3<\/jats:italic>\n                    sequence variants in cases of 46,XY disorders of sex development with XY female presentation. In vitro functional assays show that these variants disrupt ZNRF3 function. Our data reveal a sex-determining role for ZNRF3 and indicate that interactions between ZNRF3 and RSPO1 regulate mammalian sex determination.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1801223115","type":"journal-article","created":{"date-parts":[[2018,5,22]],"date-time":"2018-05-22T13:05:35Z","timestamp":1526994335000},"page":"5474-5479","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":90,"title":["ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling"],"prefix":"10.1073","volume":"115","author":[{"given":"Abigail","family":"Harris","sequence":"first","affiliation":[{"name":"Mammalian Genetics Unit, Medical Research Council, Harwell Institute, OX11 0RD Oxfordshire, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pam","family":"Siggers","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Unit, Medical Research Council, Harwell Institute, OX11 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