mTOR Controls Ovarian Follicle Growth by Regulating Granulosa Cell Proliferation

Abstract

We have shown that inhibition of mTOR in granulosa cells and ovarian follicles results in compromised granulosa proliferation and reduced follicle growth. Further analysis here using spontaneously immortalized rat granulosa cells has revealed that mTOR pathway activity is enhanced during M-phase of the cell cycle. mTOR specific phosphorylation of p70S6 kinase and 4E-BP, and expression of Raptor are all enhanced during M-phase. The predominant effect of mTOR inhibition by the specific inhibitor Rapamycin (RAP) was a dose-responsive arrest in the G1 cell cycle stage. The fraction of granulosa cells that continued to divide in the presence of RAP exhibited a dose-dependent increase in aberrant mitotic figures known as anaphase bridges. Strikingly, estradiol consistently decreased the incidence of aberrant mitotic figures. In mice treated with RAP, the mitotic index was reduced compared to controls, and a similar increase in aberrant mitotic events was noted. RAP injected during a superovulation regime resulted in a dose-dependent reduction in the numbers of eggs ovulated. Implications for the real-time regulation of follicle growth and dominance, including the consequences of increased numbers of aneuploid granulosa cells, are discussed.

PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update

“…Treatment of spontaneously immortalized rat GCs with rapamycin caused a dose-responsive arrest of cells in the G1 cell cycle stage. The fraction of GCs that continued to divide in the presence of rapamycin exhibited a dosedependent increase in aberrant mitotic figures known as anaphase bridges (Yu et al 2011). McLaughlin et al (2011 treated cultures of human ovarian cortical strips with rapamycin and observed oocyte loss characterized by empty follicles.…”

m-TOR Inhibitors in the Current Practice

“…The underlying mechanisms still remains obscure. Feng et al had found that SRL assumes a focal inhibitory part on a stem cell factor (SCF)/c-kitdependent process in spermatogonial proliferation via the PI3-K/AKT/p70S6K pathway in the animal models [96][97][98][99][100].…”

“…Further study by Yu et al had proved that inhibition of mTORi in granulosa cells and ovarian follicles resulted in compromised granulose proliferation and reduced follicle growth. Moreover, Yu and his colleagues detected increased fraction of cells that underwent anomalous mitotic events during mTOR inhibition in animal models [100].…”

“…Only two cases of successful pregnancies in 2 kidney-transplant recipients treated with EVR during pregnancy were reported. All these cases demonstrate that either SRL or EVR might not be an absolute contraindication for pregnancy, however, due to limited available data most nephrologists prefer to avoid m-TOR I therapy completely during pregnancy and advise to be discontinued and switched to CNI at least 8-12 weeks prior to attempted conception unless the potential benefit outweighs the potential risk for the fetus [24,[26][27][28]100].…”

mTORC1 et sirolimus

“…La perturbation de la prolifération de ces cellules conduit à une diminution, proportionnelle à la dose, des follicules ovulés. Cependant, ces follicules ne montrent pas d'anomalies fonctionnelles in vitro, les ovocytes peuvent être fécondés et se développer jusqu'au stade blastocyste [24]. La culture de bandes de cortex ovarien chez la femme est égale-ment sensible à la rapamycine [25].…”