Regulation of primordial follicle recruitment by cross-talk between the Notch and phosphatase and tensin homologue (PTEN)/AKT pathways

Reprod Fertil Dev. 2016 Apr;28(6):700-12. doi: 10.1071/RD14212.

Abstract

The growth of oocytes and the development of follicles require certain pathways involved in cell proliferation and survival, such as the phosphatidylinositol 3-kinase (PI3K) pathway and the Notch signalling pathway. The aim of the present study was to investigate the interaction between Notch and the PI3K/AKT signalling pathways and their effects on primordial follicle recruitment. When the Notch pathway was inhibited by L-685,458 or N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT) in vitro, the expression of genes in the pathway and the percentage of oocytes in growing follicles decreased significantly in mouse ovaries. By 2 days postpartum, ovaries exposed to DAPT, short interference (si) RNA against Notch1 or siRNA against Hairy and enhancer of split-1 (Hes1) had significantly decreased expression of HES1, the target protein of the Notch signalling pathway. In contrast, expression of phosphatase and tensin homologue (Pten), a negative regulator of the AKT signalling pathway, was increased significantly. Co immunoprecipitation (Co-IP) revealed an interaction between HES1 and PTEN. In addition, inhibition of the Notch signalling pathway suppressed AKT phosphorylation and the proliferation of granulosa cells. In conclusion, the recruitment of primordial follicles was affected by the proliferation of granulosa cells and regulation of the interaction between the Notch and PI3K/AKT signalling pathways.

MeSH terms

  • Animals
  • Cell Communication / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation, Developmental* / drug effects
  • Granulosa Cells / cytology
  • Granulosa Cells / drug effects
  • Granulosa Cells / metabolism
  • Mice
  • Oogenesis* / drug effects
  • Ovarian Follicle / cytology
  • Ovarian Follicle / drug effects
  • Ovarian Follicle / metabolism*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction* / drug effects
  • Tissue Culture Techniques
  • Transcription Factor HES-1 / antagonists & inhibitors
  • Transcription Factor HES-1 / genetics
  • Transcription Factor HES-1 / metabolism

Substances

  • Enzyme Inhibitors
  • Hes1 protein, mouse
  • Notch1 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptor, Notch1
  • Transcription Factor HES-1
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse