Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation

Abstract

The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation was that FSH regulates proliferation through a PI3K/Akt/mTORC1 pathway, and additionally, AMPK-dependent mechanisms counteract FSH proliferative effects. The present study was performed in 8-day-old rat Sertoli cell cultures. The results presented herein show that FSH, in addition to increasing p-Akt, p-mTOR, and p-p70S6K levels, increases p-PRAS40 levels, probably contributing to improving mTORC1 signaling. Furthermore, the decrease in FSH-stimulated p-Akt, p-mTOR, p-p70S6K, and p-PRAS40 levels in the presence of wortmannin emphasizes the participation of PI3K in FSH signaling. Additionally, the inhibition of FSH-stimulated Sertoli cell proliferation by the effect of wortmannin and rapamycin point to the relevance of the PI3K/Akt/mTORC1 signaling pathway in the mitotic activity of FSH. On the other hand, by activating AMPK, several interesting observations were made. Activation of AMPK produced an increase in Raptor phosphorylation, a decrease in p70S6K phosphorylation, and a decrease in FSH-stimulated Sertoli cell proliferation. The decrease in FSH-stimulated cell proliferation was accompanied by an increased expression of the cyclin-dependent kinase inhibitors (CDKIs) p19INK4d, p21Cip1, and p27Kip1. In summary, it is concluded that FSH regulates Sertoli cell proliferation with the participation of a PI3K/Akt/mTORC1 pathway and that AMPK activation may be involved in the detention of proliferation by, at least in part, a decrease in mTORC1 signaling and an increase in CDKI expression.

Hormone Signaling in the Testis

“…235 In contrast, FSH simulation of differentiating 15-to 20-day-old Sertoli cells increased cAMP levels but decreased ERK activity. 297 In other studies, FSH stimulation of 5-day-old Sertoli cells increased the levels of PIP3, a downstream target of PI3K signaling. Furthermore, inhibition of the pathway blocked Sertoli cell proliferation.…”

“…235 The FSH-mediated activation of ERK resulted in increased expression of cyclin D1 that promotes proliferation. 297 In the 8-day-old Sertoli cells, FSH stimulation also decreased activity of the AMPK that is associated with increased expression of the cell cycle inhibitors p19 INK4A , p21 Cip1 , and p27 Kip1 . 235,244,295,296 FSH also has been shown to activate the PI3K-AKT-mTORC1-p70S6K signal transduction pathway in Sertoli cells cultured from 8-day-old Sertoli cells.…”

Emerging Role for Mammalian Target of Rapamycin in Male Fertility

“…These cells express mTORC1 and mTORC2. mTORC1 is involved in FSH-mediated proliferation of in vitro cultured immature SCs, via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway, which is known to promote cell proliferation [8]. mTORC1 also regulates the redox balance of in vitro cultured human SCs, and modulates the nutritional support that these cells provide to developing germ cells [9].…”

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

“…Additionally, previous study of Tanwar et al has suggested that aberrant AMPK-mTOR signaling causes disruption of SC polarity and spermatogenesis (Tanwar et al 2012). Well-coordinated AMPK-mTOR signaling is essential for SCs functions and survival (Riera et al 2012;Tanwar et al 2012). Thus, it is important to elucidate possible contribution of AMPK-mTOR signaling to NP-induced rat SC toxicity.…”