ZFIN ID: ZDB-PUB-180509-22
ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling
Harris, A., Siggers, P., Corrochano, S., Warr, N., Sagar, D., Grimes, D.T., Suzuki, M., Burdine, R.D., Cong, F., Koo, B.K., Clevers, H., Stévant, I., Nef, S., Wells, S., Brauner, R., Ben Rhouma, B., Belguith, N., Eozenou, C., Bignon-Topalovic, J., Bashamboo, A., McElreavey, K., Greenfield, A.
Date: 2018
Source: Proceedings of the National Academy of Sciences of the United States of America   115(21): 5474-5479 (Journal)
Registered Authors: Burdine, Rebecca, Clevers, Hans, Grimes, Daniel T.
Keywords: DSD, WNT signaling, ZNRF3, organogenesis, sex determination
MeSH Terms:
  • Adolescent
  • Adult
  • Animals
  • Cells, Cultured
  • Disorders of Sex Development/genetics*
  • Disorders of Sex Development/pathology
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Gonads/metabolism
  • Gonads/pathology
  • Humans
  • Male
  • Mice
  • Mutation, Missense
  • SOX9 Transcription Factor/genetics
  • SOX9 Transcription Factor/metabolism
  • Sex Differentiation*
  • Testis/metabolism
  • Testis/pathology
  • Thrombospondins/genetics
  • Thrombospondins/metabolism
  • Ubiquitin-Protein Ligases/genetics*
  • Ubiquitin-Protein Ligases/physiology*
  • Wnt Proteins/antagonists & inhibitors*
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism
  • Young Adult
  • Zebrafish
  • beta Catenin/antagonists & inhibitors*
  • beta Catenin/genetics
  • beta Catenin/metabolism
PubMed: 29735715 Full text @ Proc. Natl. Acad. Sci. USA
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.