Abstract
While mutations in the fragile X mental retardation-1 (FMR1) gene are associated with varying reproductive outcomes in females, the effects of a complete lack of FMR1 expression are not known. Here, we studied the ovarian and reproductive phenotypes in an Fmr1 knockout (KO) mouse model and the role of mammalian target of rapamycin (mTOR) signaling. Breeding, histologic and mTOR signaling data were obtained at multiple time points in KO and wild type (WT) mice fed a control or rapamycin (mTOR inhibitor) diet. KO mice showed an earlier decline in ovarian reserve than WT mice with an increased proportion of activated follicles. mTOR and phosphorylated S6 kinase (p-S6K) levels, a measure of downstream mTOR signaling, were elevated in the KO ovaries. Rapamycin blocked these effects in KO mice, and increased the primordial follicle pool and age of last litter in WT mice. Our data demonstrates an early decline in reproductive capacity in Fmr1 KO mice and proposes that premature recruitment of the primordial pool via altered mTOR signaling may be the mechanism. Reversal of phenotypes and protein levels in rapamycin-treated KO mice, as well as increased reproductive lifespan of rapamycin-fed WT mice, suggest the mTOR pathway as a potential therapeutic target.
Highlights
Abnormalities in the fragile X mental retardation-1 (FMR1) gene located on Xq27.3 are associated with a wide array of phenotypic, neurologic and reproductive conditions[1]
The aim of our study was to examine the effects of complete silencing of the FMR1 gene on ovarian reserve and reproductive capacity using a Fmr[1] knockout (KO) mouse model
We recently demonstrated that mammalian target of rapamycin (mTOR), a protein kinase in the phosphatidylinositol 3-kinase (PI3K) pathway, is a direct target of fragile X mental retardation protein (FMRP) and that tissue from male Fragile X syndrome (FXS) patients and Fmr[1] KO mice expressed higher levels of mTOR10. mTOR is a key regulator of primordial follicle recruitment, balancing the suppressive effects of
Summary
Abnormalities in the fragile X mental retardation-1 (FMR1) gene located on Xq27.3 are associated with a wide array of phenotypic, neurologic and reproductive conditions[1]. An expansion to >200 CGG trinucleotide repeats, termed a “full mutation”, results in DNA hypermethylation of the promoter region and silencing of FMR1, leading to a deficiency in FMRP5,6 and causing Fragile X syndrome (FXS), the most common inherited cause of mental retardation and a monogenetic cause of autism[1]. Expansion to 55–200 CGG trinucleotide repeats, termed a “premutation”, results in hypomethylation of the promoter region and elevated FMR1 mRNA levels[7,8] causing fragile X-associated tremor/ataxia in males and fragile X-associated primary ovarian insufficiency (FXPOI) in females. We recently demonstrated that mTOR, a protein kinase in the phosphatidylinositol 3-kinase (PI3K) pathway, is a direct target of FMRP and that tissue from male FXS patients and Fmr[1] KO mice expressed higher levels of mTOR10. We assessed whether any observed effects in the KO mice could be reversed by administering rapamycin, an mTOR antagonist[12]
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