Figure 9.

Tsc/mTORC1 and PTEN/PI3K signaling in oocytes controls the quiescence and activation of primordial follicles in a synergistic and collaborative way. On the basis of the evidence accumulated, we propose that PTEN in oocytes suppresses follicular activation through negative regulation of the PI3K signaling and of the function of PDK1, which leads to subsequent inhibition of phosphorylation of S6K1 at T229 by PDK1 (9). On the other hand, Tsc1 in oocytes suppresses follicular activation by negative regulation of mTORC1 signaling, leading to suppressed phosphorylation of S6K1 at T389. Thus, in this scheme both PTEN and Tsc suppress the phosphorylation/activation of rpS6, but by regulating the phosphorylation of distinct threonine residues in S6K1. We propose that collaborative, synergistic functions of Tsc1–Tsc2 and PTEN are required to negatively regulate the activation of S6K1–rpS6 signaling, which in turn facilitate maintenance of the quiescence of primordial follicles. A reduction in the activities of Tsc1–Tsc2 or PTEN, or both, would lead to premature follicular activation. Also shown in the illustration is rapamycin, which is an mTORC1 specific inhibitor. P, phosphorylation; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate.