ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling
| Autor: | Silvia Corrochano, Abigail Harris, Hans Clevers, Caroline Eozenou, Isabelle Stévant, Joelle Bignon-Topalovic, Nick Warr, Neila Belguith, Sara Wells, Bochra Ben Rhouma, Pam Siggers, Serge Nef, Daniel T. Grimes, Ken McElreavey, Rebecca D. Burdine, Feng Cong, Makoto Suzuki, Andy Greenfield, Danielle Sagar, Anu Bashamboo, Bon-Kyoung Koo, Raja Brauner |
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| Přispěvatelé: | 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]-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), Université de Genève (UNIGE), Génétique du développement humain, Institut Pasteur [Paris], Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Embryo Nonmammalian Sex Differentiation Organogenesis Wnt Proteins/antagonists & inhibitors Disorders of Sex Development DSD MESH: Wnt Proteins / metabolism MESH: Testis / metabolism MESH: Disorders of Sex Development / genetics MESH: Testis / pathology MESH: Embryo Nonmammalian / cytology Mice Embryo Nonmammalian/cytology MESH: Gene Expression Regulation Developmental Testis Missense mutation MESH: Animals ddc:576.5 Developmental Disorders of sex development 10. No inequality MESH: Ubiquitin-Protein Ligases / genetics Exome sequencing Cells Cultured beta Catenin Zebrafish Multidisciplinary Cultured MESH: Thrombospondins / genetics MESH: SOX9 Transcription Factor / metabolism Wnt signaling pathway Gene Expression Regulation Developmental SOX9 Transcription Factor beta Catenin/antagonists & inhibitors MESH: beta Catenin / metabolism Sex reversal MESH: Gonads / pathology Cell biology MESH: Young Adult Embryo MESH: Gonads / metabolism Female MESH: Cells Cultured Adult Adolescent Ubiquitin-Protein Ligases Cells Thrombospondins/genetics Mutation Missense MESH: beta Catenin / antagonists & inhibitors SOX9 Biology Gonads/metabolism MESH: Embryo Nonmammalian / metabolism 03 medical and health sciences Young Adult MESH: Wnt Proteins / genetics WNT signaling medicine Animals Humans Ubiquitin-Protein Ligases/genetics MESH: SOX9 Transcription Factor / genetics MESH: Zebrafish RSPO1 Gonads General MESH: Mice Nonmammalian/cytology MESH: Disorders of Sex Development / pathology MESH: Adolescent MESH: Wnt Proteins / antagonists & inhibitors MESH: Mutation Missense MESH: Humans MESH: beta Catenin / genetics ZNRF3 MESH: Adult Sex determination medicine.disease MESH: Male MESH: Ubiquitin-Protein Ligases / physiology SOX9 Transcription Factor/genetics Wnt Proteins 030104 developmental biology MESH: Thrombospondins / metabolism [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Gene Expression Regulation Mutation Testis/metabolism Missense Thrombospondins MESH: Female Function (biology) Disorders of Sex Development/genetics MESH: Sex Differentiation |
| Zdroj: | Proceedings of the National Academy of Sciences, Vol. 115, No 21 (2018) pp. 5474-5479 Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (21), pp.5474-5479. ⟨10.1073/pnas.1801223115⟩ Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2018, 115 (21), pp.5474-5479. ⟨10.1073/pnas.1801223115⟩ Proceedings of the National Academy of Sciences of the United States of America, 115(21), 5474 Proceedings of the National Academy of Sciences of the United States of America, 115(21), 5474-5479. National Academy of Sciences |
| ISSN: | 0027-8424 1091-6490 |
| Popis: | International audience; Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways. |
| Databáze: | OpenAIRE |
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