Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer

Endocrinology. 2012 Feb;153(2):901-12. doi: 10.1210/en.2011-1347. Epub 2011 Nov 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Mullerian Hormone / genetics
  • Anti-Mullerian Hormone / metabolism
  • Cholesterol Side-Chain Cleavage Enzyme / genetics
  • Cholesterol Side-Chain Cleavage Enzyme / metabolism
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • Male
  • Mice
  • Ovary / growth & development*
  • Ovary / metabolism
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*
  • Sex Determination Processes
  • Sex-Determining Region Y Protein / genetics
  • Sex-Determining Region Y Protein / metabolism
  • Signal Transduction / physiology
  • Steroidogenic Factor 1 / metabolism*
  • Testis / growth & development
  • Testis / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • RNA, Messenger
  • SOX9 Transcription Factor
  • Sex-Determining Region Y Protein
  • Sox9 protein, mouse
  • Sry protein, mouse
  • Steroidogenic Factor 1
  • Wnt Proteins
  • beta Catenin
  • steroidogenic factor 1, mouse
  • Anti-Mullerian Hormone
  • Cholesterol Side-Chain Cleavage Enzyme