Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles.
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.
Department of Medical Biochemistry and Biophysics, Umeå University SE-901 87, Umeå, Sweden.
Deepak
D
Adhikari
Gilian
G
Flohr
Nagaraju
N
Gorre
Yan
Y
Shen
Hairu
H
Yang
Eva
E
Lundin
Zijian
Z
Lan
Michael J
MJ
Gambello
Kui
K
Liu
D000818:Animals; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009865:Oocytes / Q000378:metabolism*; D006080:Ovarian Follicle / Q000166:cytology / Q000502:physiology*; D016649:Primary Ovarian Insufficiency / Q000378:metabolism; D011506:Proteins; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D046912:Multiprotein Complexes; D011506:Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases