ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

Abigail Harris, Pam Siggers, Silvia Corrochano, Nick Warr, Danielle Sagar, Daniel T Grimes, Makoto Suzuki, Rebecca D Burdine, Feng Cong, Bon-Kyoung Koo, Hans Clevers, Isabelle Stévant, Serge Nef, Sara Wells, Raja Brauner, Bochra Ben Rhouma, Neïla Belguith, Caroline Eozenou, Joelle Bignon-Topalovic, Anu BashambooKen McElreavey, Andy Greenfield

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)5474-5479
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number21
DOIs
Publication statusPublished - 22 May 2018

Keywords

  • Adolescent
  • Adult
  • Animals
  • Cells, Cultured
  • Disorders of Sex Development/genetics
  • Embryo, Nonmammalian/cytology
  • Female
  • Gene Expression Regulation, Developmental
  • Gonads/metabolism
  • Humans
  • Male
  • Mice
  • Mutation, Missense
  • SOX9 Transcription Factor/genetics
  • Sex Differentiation
  • Testis/metabolism
  • Thrombospondins/genetics
  • Ubiquitin-Protein Ligases/genetics
  • Wnt Proteins/antagonists & inhibitors
  • Young Adult
  • Zebrafish
  • beta Catenin/antagonists & inhibitors

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