MTORC1 Signaling in oocytes is dispensable for the survival of primordial follicles and for female fertility.

Nagaraju Gorre,Rebecca Lindkvist,Deepak Adhikari,Mats Brännström,Kui Liu,Yan Shen,Haibin Wang

doi:10.1371/journal.pone.0110491

Nagaraju Gorre, Rebecca Lindkvist + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0110491

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Journal: PloS one	Publication Date: Oct 22, 2014
Citations: 61	License type: CC BY 4.0

Affiliation: University of Gothenburg

Abstract

The molecular mechanisms underlying reproductive aging and menopausal age in female mammals are poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) is a central controller of cell growth and proliferation. To determine whether mTORC1 signaling in oocytes plays a direct role in physiological follicular development and fertility in female mice, we conditionally deleted the specific and essential mTORC1 component Rptor (regulatory-associated protein of mTORC1) from the oocytes of primordial follicles by using transgenic mice expressing growth differentiation factor 9 (Gdf-9) promoter-mediated Cre recombinase. We provide in vivo evidence that deletion of Rptor in the oocytes of both primordial and further-developed follicles leads to the loss of mTORC1 signaling in oocytes as indicated by loss of phosphorylation of S6K1 and 4e-bp1 at T389 and S65, respectively. However, the follicular development and fertility of mice lacking Rptor in oocytes were not affected. Mechanistically, the loss of mTORC1 signaling in Rptor-deleted mouse oocytes led to the elevation of phosphatidylinositol 3-kinase (PI3K) signaling that maintained normal follicular development and fertility. Therefore, this study shows that loss of mTORC1 signaling in oocytes triggers a compensatory activation of the PI3K signaling cascade that maintains normal ovarian follicular development and fertility.

Highlights

In mammals, the pool of primordial follicles serves as the source of developing follicles and fertilizable ova for the entire reproductive lifespan of the organism [1]
We used a mouse model with an oocyte-specific deletion of Rptor to show that Raptor in oocytes is essential for maintaining Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling in oocytes
Follicular development and fertility in mice lacking Rptor in their oocytes were not affected by the loss of mTORC1 signaling, but phosphatidylinositol 3-kinase (PI3K) signaling was found to be elevated upon the loss of mTORC1 signaling in Rptordeleted oocytes

Summary

Introduction

The pool of primordial follicles serves as the source of developing follicles and fertilizable ova for the entire reproductive lifespan of the organism [1]. The duration of fertility and the timing of menopause are determined by the size and persistence of the primordial follicle pool [1,2,3,4]. MTORC1 consists of mTOR, Raptor, PRAS40 (proline-rich AKT substrate 40 kDa), mLST8 (mammalian lethal with sec-13 protein 8; known as GbL), and Deptor (DEP domain-containing mTOR-interacting protein) and is sensitive to rapamycin [7,8]. It has been shown that Raptor is involved in mediating mTORC1 assembly, recruiting substrates, and regulating mTORC1 activity and subcellular localization. The strength of the interaction between mTOR and Raptor can be modified by nutrients and other signals that regulate the mTORC1 pathway [9,10,11,12]

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