Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles.
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.
1Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
Deepak
D
Adhikari
Wenjing
W
Zheng
Yan
Y
Shen
Nagaraju
N
Gorre
Tuula
T
Hämäläinen
Austin J
AJ
Cooney
Ilpo
I
Huhtaniemi
Zi-Jian
ZJ
Lan
Kui
K
Liu
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D006080:Ovarian Follicle / Q000166:cytology* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016649:Primary Ovarian Insufficiency / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C519509:Crtc1 protein, mouse; C000624650:TSC1 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse