Abstract
In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR−/−) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR−/− mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR−/− female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells.
Highlights
Androgens classically mediate their genomic effects via the androgen receptor (AR), a protein encoded by an X chromosome gene, which exerts its biological function through activation of target gene expression via a sequence of processes [1,2]
We found alterations in mitochondrial morphology, biogenesis and metabolism in the granulosa cells of AR−/− mice, suggesting that ablation of AR leads to mitochondrial dysfunction
The results in this study demonstrated that pregnant mare’s serum gonadotropin (PMSG)-induced granulosa cell differentiation was impaired in AR−/− ovaries as indicated by decreasing the expression of genes involved in the granulosa cell differentiation
Summary
Androgens classically mediate their genomic effects via the androgen receptor (AR), a protein encoded by an X chromosome gene, which exerts its biological function through activation of target gene expression via a sequence of processes [1,2]. Androgens have been implicated to have a role in promoting follicular development [3,4], by up-regulating follicle-stimulating hormone (FSH) receptor (FSHR) expression and augmenting FSH-stimulated follicular differentiation [5,6,7,8]. By using Cre/LoxP system, we and others generated the global AR−/− [12,13,14] and granulosa cell-specific AR−/− female mice [15,16]. Those data showed that female mice lacking AR have a reduced fertility, fewer oocytes were recovered after superovulation with gonadotropins, and fewer corpora lutea were observed. Ablation of AR in oocytes had no effect on female fertility [15]
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