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.
Highlights
Large scale clinical investigations have begun to reveal that dietary and/or lifestyle choices can correlate with ovulatory fertility [1,2,3,4]
We asked whether the expression of mTOR signaling molecules was conserved between mouse ovary, primary mouse granulosa cells [8], and spontaneously immortalized rat granulosa cell line (SIGC) (Fig. 1)
As in mouse granulosa cells, mTOR is expressed at consistent levels in the cytoplasm in SIGC
Summary
Large scale clinical investigations have begun to reveal that dietary and/or lifestyle choices can correlate with ovulatory fertility [1,2,3,4]. We hypothesize that the mammalian Target Of Rapamycin) Serine/Threonine kinase (mTOR) is a conserved, critical factor in the production of ‘healthy’ eggs capable of giving rise to offspring. MTOR acts to integrate signals from mitogens, stress, and available nutrition [7,8]. During periods of compromised nutrition (decreased available amino acids or sugars), growth factor withdrawal, or stress, mTOR activity is decreased. This leads to reduced cell proliferation [9] and tissue growth [10], and the onset of autophagy [11]. MTOR functions as part of at least two multiprotein complexes, each of which has defined roles in the control of cell growth This leads to reduced cell proliferation [9] and tissue growth [10], and the onset of autophagy [11]. mTOR functions as part of at least two multiprotein complexes, each of which has defined roles in the control of cell growth
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