Inhibition of mTOR Signaling Pathway Delays Follicle Formation in Mice.
In mammalian ovaries, follicle assembly requires proper germ cell cyst breakdown and the invasion of somatic cells to encapsulate individual oocytes. Abnormalities in this process lead to a number of pathologies such as premature ovarian failure and infertility. As a conserved pathway regulating cell growth and metabolism in response to growth factors and nutrients, the roles of mTOR signaling in follicular development have been extensively studied in recent years. However, its functions during follicle formation remain unknown. In this study, the expression of p-rpS6 (phospho-ribosomal proteinS6), a downstream marker of mTORC1, showed dynamic changes in perinatal ovaries. When E18.5 ovaries, which mainly contained germ cell nests, were incubated with the mTOR inhibitors Rapamycin and Torin1 for 24 h, follicle assembly was delayed with differential somatic cell invasion into germ cell cyst among the groups. After transplanting treated or untreated ovaries into kidney capsules of recipient ovariectomized mice, follicular development was blocked in treated ovaries, as shown by fewer antral follicles and a higher proportion of primordial follicles. Further studies showed a significant decrease in somatic cell proliferation and the expression of marker genes related to follicular development (Kitl, Kit, Gdf9, Bmp15, Zp3, and Amhr2) in treated ovaries. Moreover, the addition of KITL, a growth factor that is mainly produced by pregranulosa cells during germ cell nest breakdown, rescued the extension of follicle formation induced by mTOR inhibitors. These results suggest that KITL functions downstream of mTOR in somatic cells to regulate their communication with oocytes during follicle formation. J. Cell. Physiol. 232: 585-595, 2017. © 2016 Wiley Periodicals, Inc.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Jing
J
Zhang
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Wenwen
W
Liu
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Xinhui
X
Sun
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Feifei
F
Kong
Department of Gynecology, Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, China.
Ye
Y
Zhu
Department of Gynecology, Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, China.
Yue
Y
Lei
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Youqiang
Y
Su
Department of Gynecology, Nanjing Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, China.
Yiping
Y
Su
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Jing
J
Li
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D038081:Organogenesis / Q000187:drug effects; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D009287:Naphthyridines; D019089:Stem Cell Factor; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus