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Culture and Co-Culture of Mouse Ovaries and Ovarian Follicles

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Published on: March 17, 2015

Inhibition of mTOR Signaling Pathway Delays Follicle Formation in Mice

Jing Zhang¹, Wenwen Liu¹, Xinhui Sun¹

¹State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Journal of Cellular Physiology

|June 16, 2016

Abstract:

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.

Insights

Mammalian ovarian follicle assembly requires somatic cell invasion. mTOR signaling inhibition delays this process and impacts fertility by affecting somatic cell proliferation and gene expression, with KITL partially rescuing the effects.

Area of Science:

Reproductive Biology
Cellular Signaling
Developmental Biology

Background:

Follicle assembly in mammalian ovaries is crucial for fertility, involving germ cell cyst breakdown and somatic cell encapsulation of oocytes.
Disruptions in follicle formation can lead to infertility and premature ovarian failure.
The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and metabolism, but its role in early follicle formation is unclear.

Purpose of the Study:

To investigate the role of mTOR signaling in the process of ovarian follicle formation in mammals.
To determine the effects of mTOR inhibition on germ cell cyst breakdown, somatic cell invasion, and subsequent follicular development.

Main Methods:

Perinatal mouse ovaries (E18.5) were cultured with mTOR inhibitors (Rapamycin, Torin1) or vehicle.
Treated and untreated ovaries were transplanted into recipient mice to assess long-term follicular development.
Somatic cell proliferation, gene expression (Kitl, Kit, Gdf9, Bmp15, Zp3, Amhr2), and the effect of KITL supplementation were analyzed.

Main Results:

mTOR inhibition delayed follicle assembly and altered somatic cell invasion into germ cell nests.
Transplanted ovaries treated with mTOR inhibitors showed blocked follicular development, with fewer antral follicles and more primordial follicles.
Somatic cell proliferation and key follicular development gene expression were significantly reduced by mTOR inhibition; KITL partially rescued these effects.

Conclusions:

mTOR signaling is essential for proper ovarian follicle formation in mammals.
KITL acts downstream of mTOR in somatic cells, mediating communication with oocytes during follicle assembly.
Dysregulation of mTOR signaling during follicle formation has detrimental effects on ovarian development and fertility.

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