mTOR controls ovarian follicle growth by regulating granulosa cell proliferation

Area of Science:

• Reproductive Biology
• Cell Cycle Regulation
• Molecular Endocrinology

Background:

• The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and proliferation.
• Granulosa cells are crucial for ovarian follicle development and function.
• Dysregulation of mTOR signaling may impact female fertility.

Purpose of the Study:

• To investigate the role of mTOR in granulosa cell cycle progression and follicle development.
• To determine the effects of mTOR inhibition on granulosa cell mitosis and ovarian follicle dynamics.
• To explore the potential influence of estradiol on mTOR-mediated effects in granulosa cells.

Main Methods:

• Utilized spontaneously immortalized rat granulosa cells and in vivo mouse models.
• Administered the mTOR inhibitor Rapamycin (RAP) to assess its impact on cell cycle phases and mitotic figures.
• Quantified cell proliferation, mitotic index, aberrant anaphase bridges, and ovulated egg numbers.

Main Results:

• mTOR pathway activity is elevated during M-phase of the cell cycle in granulosa cells.
• Rapamycin treatment caused a dose-dependent G1 cell cycle arrest and increased anaphase bridges, indicating mitotic errors.
• Estradiol administration reduced the incidence of aberrant mitotic figures.
• In vivo Rapamycin treatment decreased the mitotic index, increased aberrant mitotic events, and reduced ovulated egg numbers in a dose-dependent manner.

Conclusions:

• mTOR signaling is essential for normal granulosa cell proliferation and timely progression through the cell cycle.
• Inhibition of mTOR leads to cell cycle arrest and genomic instability in granulosa cells, impacting follicle development and ovulation.
• Estradiol may play a protective role against mTOR inhibitor-induced mitotic abnormalities.