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ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

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  • Additional Information
    • Contributors:
      Hubrecht Institute with UMC; Medical Research Coucil Harwell [Oxford, UK] (MRC Harwell); MRC Harwell; Department of Molecular Biology [Princeton]; Princeton University; Novartis Institutes for BioMedical Research (NIBR); Hubrecht Institute [Utrecht, Netherlands]; University Medical Center [Utrecht] (UMCU)-Royal Netherlands Academy of Arts and Sciences (KNAW); Université de Genève = University of Geneva (UNIGE); Fondation Ophtalmologique Adolphe de Rothschild [Paris]; Université Paris Descartes - Paris 5 (UPD5); Faculté de médecine - Faculty of Medicine [Sfax, Tunisie] (FMS); Université de Sfax - University of Sfax; Génétique du Développement humain - Human developmental genetics; Institut Pasteur [Paris] (IP); This work was supported by the Medical Research Council by core funding Grant MC_U142684167 (to A.G.) at the Harwell Institute, and the Agence Nationale de la Recherche Grant ANR-10-LABX-73 (to K.M.). S.N. acknowledges support from Swiss National Science Foundation Grant 31003A_173070. M.S. was a visiting scientist supported by the Strategic International Research Exchange Program between Princeton University and National Institutes of Natural Sciences, Japan. D.T.G. was supported by National Institute of Arthritis and Mucoskeletal and Skin Diseases Pathway to Independence Award 1K99AR070905. Work in the R.D.B. laboratory is supported by the National Institute of Child Health and Development Grant 2R01HD048584.; We thank the husbandry team in Ward 5 of the Mary Lyon Centre at Harwell and the Frozen Embryo and Sperm Archive (FESA) and histology teams. We thank Dagmar Wilhelm for the kind gift of anti-FOXL2 antibody. We thank Phil Johnson for zebrafish husbandry. We acknowledge European Cooperation in Science & Technology (COST) Action BM1303 (DSDnet).; ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010); University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW); Université de Genève (UNIGE); Génétique du développement humain; Institut Pasteur [Paris]
    • Publication Information:
      Proceedings of the National Academy of Sciences, 2018.
    • Publication Date:
      2018
    • Abstract:
      Significance Sex determination involves antagonistic interactions between the testis-determining (SRY-SOX9-FGF9) and ovary-promoting (RSPO1-WNT/β-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 ZNRF3 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.
    • File Description:
      application/pdf
    • ISSN:
      1091-6490
      0027-8424
    • Accession Number:
      10.1073/pnas.1801223115
    • Rights:
      CC BY NC ND
    • Accession Number:
      edsair.doi.dedup.....f785b7c346bbb98027161ca7382405e7