File:Primordial follicle activation signaling model.jpg

Primordial follicle activation signaling model

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.

Original file name: Figure 9. F9.medium.jpg

Reference

<pubmed>19843540</pubmed>| Hum Mol Genet.

"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."

© The Author 2009. Published by Oxford University Press This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.