Human Molecular Genetics Advance Access [Accepted Manuscript] published online on October 20, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp483
Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
1 Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden 2 Department of Physiology, Institute of Biomedicine, University of Turku, 20520 Turku, Finland 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA 4 Department of Reproductive Biology, Imperial College London, Hammersmith Campus, London W12 0NN, UK 5 Birth Defects Center, Department of Molecular, Cellular and Craniofacial Biology, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
* To whom correspondence should be addressed. Tel: +46-90-7867762; Fax: +46-90-7865450; E-mail: kui.liu{at}medchem.umu.se
Received August 15, 2009; Revised October 18, 2009; Accepted October 18, 2009
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 Tsc1 (tuberous sclerosis complex 1), which negatively regulates mTORC1 (mammalian target of rapamycin complex 1), 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 ten), 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.