title: Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer.
abstract: Genome analysis of patients with disorders of sex development, and gain- and loss-of-function studies in mice indicate that gonadal development is regulated by opposing signals. In females, the Wnt/β-catenin canonical pathway blocks testicular differentiation by repressing the expression of the Sertoli cell-specific gene Sox9 by an unknown mechanism. Using cell and embryonic gonad culture models, we show that activation of the Wnt/β-catenin pathway inhibits the expression of Sox9 and Amh, whereas mRNA and protein levels of Sry and steroidogenic factor 1 (Sf1), two key transcriptional regulators of Sox9, are not altered. Ectopic activation of Wnt/β-catenin signaling in male gonads led to a loss of Sf1 binding to the Tesco enhancer and absent Sox9 expression that we also observed in wild-type ovaries. Moreover, ectopic Wnt/β-catenin signaling induced the expression of the female somatic cell markers, Bmp2 and Rspo1, as a likely consequence of Sox9 loss. Wnt/β-catenin signaling in XY gonads did not, however, affect gene expression of the steroidogenic Leydig cell Sf1 target gene, Cyp11a1, or Sf1 binding to the Cyp11a1 promoter. Our data support a model in ovary development whereby activation of β-catenin prevents Sf1 binding to the Sox9 enhancer, thereby inhibiting Sox9 expression and Sertoli cell differentiation.
authors: Prince Henry's Institute of Medical Research, Monash Medical Centre, P.O. Box 5152, Clayton, Melbourne 3168, Australia.
authors: Pascal
authors: P
authors: Bernard
authors: Janelle
authors: J
authors: Ryan
authors: Helena
authors: H
authors: Sim
authors: Daniel P
authors: DP
authors: Czech
authors: Andrew H
authors: AH
authors: Sinclair
authors: Peter
authors: P
authors: Koopman
authors: Vincent R
authors: VR
authors: Harley
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008297:Male; D051379:Mice; D010053:Ovary / Q000254:growth & development* / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D019849:Sex Determination Processes; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D054339:Steroidogenic Factor 1 / Q000378:metabolism*; D013737:Testis / Q000254:growth & development / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; D051876:Sex-Determining Region Y Protein; C527933:Sox9 protein, mouse; C497746:Sry protein, mouse; D054339:Steroidogenic Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; C515058:steroidogenic factor 1, mouse; D054304:Anti-Mullerian Hormone; D002786:Cholesterol Side-Chain Cleavage Enzyme