Abstract
Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor negatively regulating mammalian target of rapamycin complex 1 (mTORC1). It is reported that mice lacking Tsc1 gene in oocytes show depletion of primordial follicles, resulting in premature ovarian failure and subsequent infertility. A recent study indicated that deletion of Tsc1 in somatic cells of the reproductive tract caused infertility of female mice. However, it is not known whether specific disruption of Tsc1 in granulosa cells influences the reproductive activity of female mice. To clarify this problem, we mated Tsc1flox/flox mice with transgenic mice strain expressing cyp19-cre which exclusively expresses in granulosa cells of the ovary. Our results demonstrated that Tsc1flox/flox; cyp19-cre mutant mice were fertile, ovulating more oocytes and giving birth to more pups than control Tsc1flox/flox mice. Progressive accumulation of corpora lutea occurred in the Tsc1flox/flox; cyp19-cre mutant mice with advanced age. These phenotypes could be explained by the elevated activity of mTORC1, as indicated by increased phosphorylation of rpS6, a substrate of S6 in the Tsc1flox/flox; cyp19-cre mutant granulosa cells. In addition, rapamycin, a specific mTORC1 inhibitor, effectively rescued the phenotype caused by increased mTORC1 activity in the Tsc1cko ovaries. Our data suggest that conditional knockout of Tsc1 in granulosa cells promotes reproductive activity in mice.
Highlights
IntroductionFolliculogenesis is strictly controlled by FSH and LH. FSH supports follicles to develop to the preovulatory stage, and the LH surge causes ovulation and rapidly initiates terminal differentiation of ovulated follicles into the corpora lutea [1,2]
In mammals, folliculogenesis is strictly controlled by FSH and LH
First we compared the expression of TSC1 protein in the granulosa cells of control and mutant ovaries, to confirm that the expression of TSC1 was diminished in the mutant granulosa cells
Summary
Folliculogenesis is strictly controlled by FSH and LH. FSH supports follicles to develop to the preovulatory stage, and the LH surge causes ovulation and rapidly initiates terminal differentiation of ovulated follicles into the corpora lutea [1,2]. Numerous signaling pathways participate in these processes, such as phosphoinositide-3 kinase (PI3K), ERK1/2 and CAMP/protein kinase A pathways. These pathways coordinate expression of a huge number of genes in granulosa cells stimulated by FSH and LH [3]. Conditional knockout of Pten in ovary granulosa cells promotes ovulation and causes progressive accumulation of corpora lutea [14]. These results indicate that the PI3K pathway is very important for ovarian functions
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