PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles

Abstract

The molecular mechanisms that control reproductive aging and menopausal age in females are poorly understood. Here, we provide genetic evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) signaling in oocytes preserves reproductive lifespan by maintaining the survival of ovarian primordial follicles. In mice lacking the PDK1-encoding gene Pdk1 in oocytes, the majority of primordial follicles are depleted around the onset of sexual maturity, causing premature ovarian failure (POF) during early adulthood. We further showed that suppressed PDK1-Akt-p70 S6 kinase 1 (S6K1)-ribosomal protein S6 (rpS6) signaling in oocytes appears to be responsible for the loss of primordial follicles, and mice lacking the Rps6 gene in oocytes show POF similar to that in Pdk1-deficient mice. In combination with our earlier finding that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in oocytes suppresses follicular activation, we have now pinpointed the molecular network involving phosphatidylinositol 3 kinase (PI3K)/PTEN-PDK1 signaling in oocytes that controls the survival, loss and activation of primordial follicles, which together determine reproductive aging and the length of reproductive life in females. Underactivation or overactivation of this signaling pathway in oocytes is shown to cause pathological conditions in the ovary, including POF and infertility.

Blocking the PI3K pathway or the presence of high concentrations of EGF inhibits the spontaneous activation of ovine primordial follicles in vitro

“…Therefore, to verify the involvement of the PI3K in the regulation of ovine primordial follicle activation in vitro, we tested the hypothesis that pharmacological inhibition of the PI3K pathway with LY294002 would inhibit the initiation of follicle growth. LY294002 has been used at different concentrations (from 1 μM to 50 μM) and incubation periods (from 20 min to 14 days) to inhibit the PI3K pathway in different ovarian cells (Reddy et al, 2009;Mani et al, 2010;Adhikari et al, 2013;Zhang et al, 2014;Fujihara et al, 2014;Lan et al, 2017). In this study, although the concentration of the inhibitor (50 µM LY294002) is higher than most of the other studies (Keating et al, 2009;Sobinoff et al, 2012;Zhang et al, 2014;Zhao et al, 2017), our findings support the idea that this concentration was not toxic because it did not reduce the percentage of normal follicles compared to the treatment without the inhibitor.…”

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

“…37 Survival of mouse primordial follicles requires PI3K, phosphoinositide-dependent protein kinase-1 (PDK1), and S6k1, which are members of the insulin signaling cascade. 38 Treatment with rapamycin, a drug known to block Tor activity, inhibits oocyte growth in cultured Drosophila and mammalian ovaries, and leads to apoptosis and autophagy. 37,39,40,26 Taken together, these findings suggest an evolutionarily conserved role for insulin and Tor signaling in promoting survival in the ovary.…”

Molecular alterations during female reproductive aging: Can aged oocytes remind youth?

“…For the survival of primordial follicles, 3-phosphoinositide-dependent protein kinase-1 (PDK1) in oocytes preserves the lifespan by maintaining the ovarian follicle pool (Reddy et al 2009). PDK1 and PTEN have been reported to be critical regulators in the phosphatidylinositol 3-kinase (PI3K) www.intechopen.com signaling pathway (Iwanami et al 2009).…”