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

TitleZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling.
Publication TypeJournal Article
Year of Publication2018
AuthorsHarris, A, Siggers, P, Corrochano, S, Warr, N, Sagar, D, Grimes, DT, Suzuki, M, Burdine, RD, 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
JournalProc Natl Acad Sci U S A
Date Published2018 05 22
KeywordsAdolescent, Adult, Animals, beta Catenin, Cells, Cultured, Disorders of Sex Development, Embryo, Nonmammalian, Female, Gene Expression Regulation, Developmental, Gonads, Humans, Male, Mice, Mutation, Missense, Sex Differentiation, SOX9 Transcription Factor, Testis, Thrombospondins, Ubiquitin-Protein Ligases, Wnt Proteins, Young Adult, Zebrafish

<p>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 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human 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.</p>

Alternate JournalProc Natl Acad Sci U S A
PubMed ID29735715
PubMed Central IDPMC6003506
Grant ListK99 AR070905 / AR / NIAMS NIH HHS / United States
MC_UP_1502/1 / MRC_ / Medical Research Council / United Kingdom
R01 HD048584 / HD / NICHD NIH HHS / United States
MC_U142684167 / MRC_ / Medical Research Council / United Kingdom