Rspo1 dependent WNT signaling safeguards ovarian development by suppressing androgen signaling

Furong Tang; Natividad Bellido-Carreras; Kheira Bouzid; Aurélie Lardenois; Thomas Darde; Magali Dhellemmes; Aurelie Despoux; Mirko Peitzsch; Marie‐Christine Birling; Frédéric Chalmel; Marie‐Christine Chaboissier; Aitana Perea-Gómez

doi:10.64898/2026.09.22.753168

Developmental BiologybioRxivSep 23, 2026

Preprint

Rspo1 dependent WNT signaling safeguards ovarian development by suppressing androgen signaling

Furong Tang iD, Natividad Bellido-Carreras iD, Kheira Bouzid iD, Aurélie Lardenois iD, Thomas Darde iD, Magali Dhellemmes iD, Aurelie Despoux, Mirko Peitzsch iD, Marie‐Christine Birling iD, Frédéric Chalmel iD, Marie‐Christine Chaboissier iD, Aitana Perea-Gómez iD

Abstract

Embryonic ovarian development requires high levels of WNT/B-catenin signaling yet the molecular basis of this requirement remains unclear. Mutations in the WNT potentiator RSPO1 impair ovarian development in both mouse and human, leading to gonadal masculinization in XX individuals. Here, we show that RSPO1 acts within a restricted developmental window at the onset of ovarian differentiation and that its absence triggers precocious androgen signaling in the developing ovaries. Moreover, androgen receptor inhibition rescues ovarian development in Rspo1 mutant mice. Our findings identify RSPO1/WNT/B-catenin signaling as an essential pathway that suppresses androgen signaling to ensure proper ovarian development in mouse.

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