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Proc Natl Acad Sci U S A. 2018 May 22;115(21):5474-5479. doi: 10.1073/pnas.1801223115. Epub 2018 May 7.

ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling.

Author information

1
Mammalian Genetics Unit, Medical Research Council, Harwell Institute, OX11 0RD Oxfordshire, United Kingdom.
2
Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
3
Novartis Institutes for Biomedical Research, Cambridge, MA 02139.
4
Hubrecht Institute, University Medical Center, 3584 CT Utrecht, The Netherlands.
5
Department of Genetic Medicine and Development, University of Geneva Medical School, CH 1211 Geneva 4, Switzerland.
6
The Mary Lyon Centre, Medical Research Council Harwell Institute, OX11 0RD Oxfordshire, United Kingdom.
7
Université Paris Descartes and Paediatric Endocrinology Unit, Fondation Opthalmologique Adolphe de Rothschild, 75019 Paris, France.
8
Human Molecular Genetics Laboratory, Faculty of Medicine, University of Sfax, 3030 Sfax, Tunisia.
9
Human Developmental Genetics, Institut Pasteur, 75724 Paris, France.
10
Human Developmental Genetics, Institut Pasteur, 75724 Paris, France kenneth.mcelreavey@pasteur.fr a.greenfield@har.mrc.ac.uk.
11
Mammalian Genetics Unit, Medical Research Council, Harwell Institute, OX11 0RD Oxfordshire, United Kingdom; kenneth.mcelreavey@pasteur.fr a.greenfield@har.mrc.ac.uk.

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.

KEYWORDS:

DSD; WNT signaling; ZNRF3; organogenesis; sex determination

PMID:
29735715
PMCID:
PMC6003506
DOI:
10.1073/pnas.1801223115
[Indexed for MEDLINE]
Free PMC Article

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