FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice

FASEB J. 2014 May;28(5):2020-8. doi: 10.1096/fj.13-246108. Epub 2014 Jan 22.


Steroidogenic factor 1 (SF1; Ad4BP/NR5A1) plays key roles in gonadal development. Initially, the Sf1 gene is expressed in mouse fetal gonads of both sexes, but later is up-regulated in testes and down-regulated in ovaries. While Sf1 expression is activated and maintained by Wilms tumor 1 (WT1) and LIM homeobox 9 (LHX9), the mechanism of sex-specific regulation remains unclear. We hypothesized that Sf1 is repressed by the transcription factor Forkhead box L2 (FOXL2) during ovarian development. In an in vitro system (TM3 cells), up-regulation of Sf1 by the WT1 splice variant WT1-KTS was antagonized by FOXL2, as determined by quantitative RT-PCR. Using reporter assays, we localized the Sf1 proximal promoter region involved in this antagonism to a 674-bp interval. A conserved FOXL2 binding site was identified in this interval by in vitro chromatin immunoprecipitation. Introducing mutations into this site abolished negative regulation by FOXL2 in reporter assays. Finally, in Foxl2-null mice, Sf1 expression was increased 2-fold relative to wild-type XX fetal gonads. Our results support the hypothesis that FOXL2 negatively regulates Sf1 expression by antagonizing WT1-KTS during early ovarian development in mice.

Keywords: LHX9; reproduction; sex determination.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Differentiation
  • Female
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Developmental*
  • Genes, Reporter
  • LIM-Homeodomain Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mutagenesis
  • Mutation
  • Ovary / embryology*
  • Ovary / metabolism
  • Plasmids / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroidogenic Factor 1 / metabolism
  • Time Factors
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • WT1 Proteins / antagonists & inhibitors
  • WT1 Proteins / metabolism*


  • Forkhead Box Protein L2
  • Forkhead Transcription Factors
  • Foxl2 protein, mouse
  • LIM-Homeodomain Proteins
  • Lhx9 protein, mouse
  • Steroidogenic Factor 1
  • Transcription Factors
  • WT1 Proteins
  • steroidogenic factor 1, mouse