Crosstalk between FSH and relaxin at the end of the proliferative stage of rat Sertoli cells

Abstract

Follicle-stimulating hormone (FSH) stimulates the proliferation of immature Sertoli cells through the activation of PI3K/AKT/mTORC1 and MEK/ERK1/2 pathways. Mature Sertoli cells stop proliferating and respond to FSH by stimulating cAMP production. To gain insight into possible mechanisms involved in this switch as well as the impact of paracrine factors that stimulate cell proliferation, we analyzed the effects of FSH and relaxin on intracellular signaling pathways involved with proliferation and differentiation in Sertoli cells from 15-day-old rats, which are close to the transition between the two stages. FSH stimulated H-thymidine incorporation and cyclin D1 expression, changes associated with proliferation. In contrast, FSH inhibited AKT and ERK1/2 phosphorylation, activated cAMP production and induced changes in several cell cycle genes that were compatible with differentiation. Relaxin also stimulatedH-thymidine incorporation but increased phosphorylation of ERK1/2 and AKT. When both hormones were added simultaneously, relaxin attenuated FSH-mediated inhibition of ERK1/2 and AKT phosphorylation and FSH-mediated activation of cAMP production. FSH but not relaxin increased CREB phosphorylation, and relaxin but not FSH shifted NF-κB expression from the cytoplasm to the nucleus. Relaxin did not inhibit the effects of FSH on inhibin α and Bcl2 expression. We propose that at this time of Sertoli cell development, FSH starts to direct cells to differentiation through activation of cAMP/CREB and inhibition of ERK1/2 and AKT pathways. Relaxin counteracts FSH signaling through the inhibition of cAMP and activation of ERK1/2, AKT and NF-κB, but does not block the differentiation process triggered by FSH.

Effect of resveratrol on Sertoli cell proliferation

“…The role of FSH in Sertoli cell proliferation has been largely investigated. 18,31,[38][39][40][41][42] Considering that FSH regulates Sertoli cell proliferation during fetal and postnatal life, it is important to analyze factors that might counteract FSH In the present investigation, we show that RSV suppresses FSH-stimulated Sertoli cell proliferation. As for the regulation by FSH of the regulators of G1/S cell cycle transition, it has been shown that FSH can regulate, either directly or indirectly, Sertoli cell cyclins D1 and D2 levels in different experimental models.…”

“…18,31,[38][39][40][41][42] Considering that FSH regulates Sertoli cell proliferation during fetal and postnatal life, it is important to analyze factors that might counteract FSH RNA was extracted and RT-qPCR was performed. 18,31,[38][39][40][41][42] Considering that FSH regulates Sertoli cell proliferation during fetal and postnatal life, it is important to analyze factors that might counteract FSH RNA was extracted and RT-qPCR was performed.…”

Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation

“…Supporting the hypothesis that relaxin has a role on Sertoli cell proliferation, it has been observed that KO mice for this gene have smaller testes (77). More recently, a crosstalk between FSH and relaxin at the end of the proliferative stage in rat Sertoli cells was demonstrated, and the authors postulate that whereas FSH action predominates and seems essential to direct cell maturation, relaxin seems to preferentially promote Sertoli cell proliferation (78, 79).…”

E4 Transcription Factor 1 (E4F1) Regulates Sertoli Cell Proliferation and Fertility in Mice

“…Sertoli cell proliferation is regulated by hormones, growth factors and cytokines during fetal and neonatal period of development. FSH stimulates Sertoli cell proliferation by activating cAMP/PKA/ERK1/2 and P13K/Akt/mTORC1 dependent-pathway [ 49 ]. Relaxin increases the levels of proliferating cell nuclear antigen (PCNA) in Sertoli cell cultures by activating P13K/Akt and ERK1/2 pathway [ 50 ].…”