Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles

Abstract

To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.

Rictor/mTORC2 Pathway in Oocytes Regulates Folliculogenesis, and Its Inactivation Causes Premature Ovarian Failure

“…For example, deletion of Pten from mouse oocytes causing overactivation of PI3K signaling leads to premature activation of the entire pool of primordial follicles (16). Deletion of Tsc1 (20) or Tsc2 (21) in oocytes induces overactivation of mTORC1 signaling and results in global activation of all primordial follicles around the time of puberty, ending with follicular depletion in early adulthood. In contrast, POF of Rictor-cKO mice was caused by excessive follicular atresia, which occurred at every developmental stage, rather than entire overactivation of the primordial follicle pool in the three mutant mice.…”

Follicular assembly: mechanisms of action

“…TSC1/2 and MTOR may be activated during cyst breakdown within oocytes. Few studies have examined the role of these molecules in follicle development, but TSC1 was recently shown to be important in primordial follicle activation using Tsc1 knockout mice (Adhikari et al 2010). Oocyte-specific knockouts of Tsc1 or Pten (a negative regulator of PI3K signaling) undergo normal primordial follicle formation (Reddy et al 2008, Adhikari et al 2010.…”

“…Few studies have examined the role of these molecules in follicle development, but TSC1 was recently shown to be important in primordial follicle activation using Tsc1 knockout mice (Adhikari et al 2010). Oocyte-specific knockouts of Tsc1 or Pten (a negative regulator of PI3K signaling) undergo normal primordial follicle formation (Reddy et al 2008, Adhikari et al 2010. However, in these studies, the Gdf9 promoter was used to drive Cre recombinase in oocytes, and this promoter is not active until PND3 after most cysts have already broken down (Lan et al 2004).…”

All Your Eggs in One Basket: Mechanisms of Xenobiotic Induced Female Reproductive Senescence

“…Therefore, in addition to acting synergistically with mTOR signalling to cause primordial follicle activation, PI3k/Akt signalling may help preserve the primordial follicle pool in times of cytotoxic stress. Interestingly however, mTOR signalling does not require PI3k/Akt signalling to induce primordial follicle activation, and in fact may be the sole driver of DMBA induced primordial follicle activation (Adhikari et al, 2010). Fig.…”