title: Rapamycin-sensitive mTORC1 signaling is involved in physiological primordial follicle activation in mouse ovary.
abstract: In mammals, resting female oocytes reside in primordial ovarian follicles. An individual primordial follicle may stay quiescent for a protracted period of time before initiating follicular growth, which is also termed “activation.” Female reproductive capacity is sustained by the gradual, streamlined activation of the entire population of primordial follicles, but this process also results in reproductive senescence in older animals. Based on the recent findings that genetically triggered, excessive mammalian target of rapamycin complex 1 (mTORC1) activation in mouse oocytes leads to accelerated primordial follicle activation, we examined the necessity of mTORC1 signaling in physiological primordial follicle activation. We found that induction of oocyte mTORC1 activity is associated with early follicular growth in neonatal mouse ovaries. Pharmacological inhibition of mTORC1 activity in vivo by rapamycin treatment leads to a marked, but partial, suppression of primordial follicle activation. The suppressive effect of rapamycin on primordial follicle activation was reproduced in cultured ovaries. While rapamycin did not apparently affect several plausible cellular targets in neonatal mouse ovaries, such as mTORC2, AKT, or cyclin-dependent kinase (CDK) inhibitor p27-KIP1, its inhibitory effect on Cyclin A2 gene expression implies that mTORC1 signaling in oocytes may engage a Cyclin A/CDK regulatory network that promotes primordial follicle activation. The current work strengthens the concept that mTORC1-dependent events in the oocytes of primordial follicles may represent potential targets for intervention in humans to slow the depletion of the ovarian reserve.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Tong
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Cao
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.forename: Jianghuai
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D056751:Cyclin A2 / Q000096:biosynthesis / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D005260:Female; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology*; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000254:growth & development*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C508184:CCNA2 protein, mouse; D056751:Cyclin A2; D046912:Multiprotein Complexes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D020123:Sirolimus