Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary.
The sex of an individual is determined by the fate of the gonad. While the expression of Sry and Sox9 is sufficient to induce male development, we here show that female differentiation requires activation of the canonical beta-catenin signaling pathway. beta-catenin activation is controlled by Rspo1 in XX gonads and Rspo1 knockout mice show masculinized gonads. Molecular analyses demonstrate an absence of female-specific activation of Wnt4 and as a consequence XY-like vascularization and steroidogenesis. Moreover, germ cells of XX knockout embryos show changes in cellular adhesions and a failure to enter XX specific meiosis. Sex cords develop around birth, when Sox9 becomes strongly activated. Thus, a balance between Sox9 and beta-catenin activation determines the fate of the gonad, with Rspo1 acting as a crucial regulator of canonical beta-catenin signaling required for female development.
Chassot
Anne-Amandine
AA
INSERM, U636, F-06108 Nice, France.
Ranc
Fariba
F
Gregoire
Elodie P
EP
Roepers-Gajadien
Hermien L
HL
Taketo
Makoto M
MM
Camerino
Giovanna
G
de Rooij
Dirk G
DG
Schedl
Andreas
A
Chaboissier
Marie-Christine
MC
D000818:Animals; D002454:Cell Differentiation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005854:Germ Cells / Q000166:cytology / Q000502:physiology; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000166:cytology* / Q000254:growth & development; D055758:SOX9 Transcription Factor; D019849:Sex Determination Processes; D012733:Sex Differentiation; D015398:Signal Transduction; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein; D051176:beta Catenin / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D006609:High Mobility Group Proteins; C518903:RSPO1 protein, mouse; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D019699:Thrombospondins; D014157:Transcription Factors; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin