Mol. Hum. Reprod. Advance Access originally published online on October 20, 2009
Molecular Human Reproduction 2009 15(12):765-770; doi:10.1093/molehr/gap092
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This article appears in the following Molecular Human Reproduction issue: Special Issue: The ovary: from basic research to clinic [View the issue table of contents]
Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles
1Department of Medical Biochemistry and Biophysics, Umeå University SE-901 87, Umeå, Sweden 2 Hogeschool Leiden, Zernikedreef 11, 2333 CK Leiden, The Netherlands 3Medical Biosciences/Pathology, Umeå University SE-901 87, Umeå, Sweden 4 University of Louisville Health Sciences Center, Louisville, KY, USA 5 University of Texas Health Science Center at Houston, Department of Pediatrics, Houston, Texas, USA
6 Correspondence address. E-mail: deepak.adhikari{at}medchem.umu.se
To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1–Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.
Key words: follicular activation/oocytes/Tsc/mTOR signaling/premature ovarian failure
These authors equally contributed to this article. Submitted on October 9, 2009; resubmitted on October 16, 2009; accepted on October 17, 2009.