FMR1 and AKT/mTOR Signaling in Human Granulosa Cells: Functional Interaction and Impact on Ovarian Response.

Julia Rehnitz,Peter H Vogt,Jens Erik Dietrich,Ariane Germeyer,Alexander Freis,Birgitta Messmer,Thomas Strowitzki,Xuan Phuoc Nguyen,Edison Capp,Karin Hinderhofer

doi:10.3390/jcm10173892

Abstract

We aimed to determine whether a functional link with impact on female ovarian reserve exists between FMR1 expression and expression ratios of AKT/mTOR signaling genes in human granulosa cells in vivo, as suggested from prior in vitro data. Three hundred and nine women, who were classified as normal (NOR; n = 225) and poor (POR; n = 84) responders based on their ovarian reserve, were recruited during stimulation for assisted reproductive techniques. Expressions of FMR1 and of key genes of the AKT/mTOR and AKT/FOXO1/3 signaling pathways were comparatively analyzed in their granulosa cells. FMR1 expression in granulosa cells of NOR and POR correlated significantly with AKT1, TSC2, mTOR, and S6K expression. No correlation was found between FMR1 and FOXO1 in all, and FOXO3 expression in POR, patients. AKT1 expression was significantly higher and FOXO1 expression lower in POR samples, whereas AKT1 expression was lower and FOXO1 expression was higher in NOR samples. In human native granulosa cells, FMR1 expression significantly correlated with the expression of key genes of the AKT/mTOR signaling pathway, but not with the FOXO1/3 signaling pathway. Our data point to a functional link between FMR1 expression and expression of the AKT/mTOR signaling pathway genes controlling human follicular maturation.

Highlights

Controlled ovarian follicular maturation after puberty is essential for successful reproduction
Elevated FMR1 expression analyzed in native granulosa cells (GCs) of women with distinct ovarian responses demonstrated an association with poor ovarian reserve in women with CGG repeats below the norm of 26–34 repeats [17]
We demonstrated that FMR1 expression in native human GCs in women with different ovarian responses is significantly and positively correlated with the expression levels of AKT1, tuberous sclerosis protein 2 (TSC2), mTOR, and S6K

Summary

Introduction

Controlled ovarian follicular maturation (folliculogenesis) after puberty is essential for successful reproduction It results in an individual ovarian reserve dependent on age [1]. When women with DOR undergo controlled ovarian stimulation during ART, there is an increased risk of poor ovarian response leading to a reduced number of mature follicles. CGG triplet repeats between 54 and 200 are termed as “premutation” (PM), because this longer CGG block becomes subsequently unstable during further heredity and may lead to transmission of a full mutation (FM) allele with >200 CGG repeats in the generation In such cases, FMR1 is silenced due to complete CpG methylation of its promoter domain, causing fragile X syndrome (FXS; OMIM #300624) [8]. We discovered that the FMR1 transcription rate in human GCs is dependent on epigenetic factors, namely, CpG methylation patterns in three distinct genomic regions, designated as VMR1–3 (variably methylated regions) [21]

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