Wnt/β-catenin signaling regulates follicular development by modulating the expression of Foxo3a signaling components

Mol Cell Endocrinol. 2014 Feb 15;382(2):915-25. doi: 10.1016/j.mce.2013.11.007. Epub 2013 Nov 15.


Wnt signaling is an evolutionarily conserved pathway that regulates cell proliferation, differentiation and apoptosis. To investigate the possible role of Wnt signaling in the regulation of ovarian follicular development, secondary follicles were isolated and cultured in vitro in the presence or absence of its activator (LiCl or Wnt3a) or inhibitor (IWR-1). We have demonstrated that activation of β-catenin signals by activators dramatically suppressed follicular development by increasing granulosa cell apoptosis and inhibiting follicle steroidogenesis. In contrast, inhibition of Wnt signaling by IWR-1 was observed with better developed follicles and increased steroidogenesis. Further studies have shown that the transcription factor Forkhead box O3a (Foxo3a) and its downstream target molecules were modulated by the activators or the inhibitor. These findings provide evidence that Wnt signaling might negatively regulate follicular development potentially through Foxo3a signaling components.

Keywords: 3β-HSD; 3β-hydroxysteroid dehydrogenase; APC; CTNNB1; CYP11A1; CYP19A1; DMSO; FBS; FZD; Follicle culture; Forkhead box O; Foxo; Foxo3a; GSK3β; HMG-domain; IWR; IWR-1; LRP; LiCl; P450 cholesterol side chain cleavage; PUMA; StAR; T-cell factor/lymphoid enhancer-binding protein; TCF/LEF; TUNEL; Wnt; Wnt/β-catenin signaling; Wnt3a; adenomatosis polyposis coli; cytochrome P450 aromatase; dimethylsulfoxide; fetal bovine serum; frizzled; glycogen synthase kinase 3β; high mobility group domain; inhibitors of Wnt response; lipoprotein receptor-related proteins; p53-upregulated modulator of apoptosis; steroidogenic acute regulatory protein; terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling; wingless-type mouse mammary tumor virus integration site family; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Female
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Developmental
  • Imides / pharmacology
  • Lithium Chloride / pharmacology
  • Mice
  • Ovarian Follicle / cytology
  • Ovarian Follicle / drug effects
  • Ovarian Follicle / growth & development
  • Ovarian Follicle / metabolism*
  • Primary Cell Culture
  • Quinolines / pharmacology
  • Signal Transduction*
  • Steroids / biosynthesis
  • Wnt3A Protein / genetics*
  • Wnt3A Protein / metabolism
  • Wnt3A Protein / pharmacology
  • beta Catenin / genetics*
  • beta Catenin / metabolism


  • CTNNB1 protein, mouse
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • IWR-1 compound
  • Imides
  • Quinolines
  • Steroids
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • Lithium Chloride