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

Area of Science:

• Reproductive biology
• Molecular endocrinology
• Genetics

Background:

• Steroidogenic factor 1 (SF1) is crucial for gonadal development, with its expression differing between sexes postnatally.
• The precise mechanisms governing sex-specific regulation of SF1, particularly its downregulation in ovaries, are not fully understood.

Purpose of the Study:

• To investigate the role of Forkhead box L2 (FOXL2) in the sex-specific regulation of Steroidogenic factor 1 (SF1) during mouse ovarian development.
• To elucidate the molecular mechanism by which FOXL2 influences SF1 expression.

Main Methods:

• Quantitative RT-PCR and reporter assays in TM3 cells to assess SF1 regulation by FOXL2 and WT1-KTS.
• Chromatin immunoprecipitation to identify FOXL2 binding sites within the SF1 promoter.
• Analysis of SF1 expression in Foxl2-null mice.

Main Results:

• FOXL2 antagonizes the up-regulation of SF1 by the WT1-KTS splice variant in vitro.
• A specific FOXL2 binding site in the SF1 proximal promoter was identified and shown to be essential for FOXL2-mediated repression.
• SF1 expression was significantly increased in the fetal ovaries of mice lacking FOXL2.

Conclusions:

• FOXL2 negatively regulates SF1 expression during early ovarian development in mice.
• This repression is mediated by FOXL2 antagonizing WT1-KTS activity at the SF1 promoter.
• FOXL2 plays a critical role in establishing the female-specific expression pattern of SF1.