Mechanisms involved in the homologous down-regulation of transcription of the follicle-stimulating hormone receptor gene in Sertoli cells

Abstract

The action of follicle-stimulating hormone (FSH) in spermatogenesis is regulated at a fundamental level by controlling the number of competent receptors present at the surface of Sertoli cells. By controlling the number of receptors, the cell is able to modulate the timing and magnitude of subsequent signal transduction in response to FSH. One mechanism of control is the down-regulation of the steady state levels of the FSH receptor gene after exposure to FSH or agents that stimulate or prolong the cAMP signal transduction cascade (homologous down-regulation) in Sertoli cells. The goals of this study were to examine possible mechanisms involved in the down-regulation of mRNA levels of this gene. Analysis of transcription and processing by a PCR-based assay showed that treatment of Sertoli cells with FSH caused at least a 50% reduction of hnRNA for the FSH receptor gene. Reporter genes controlled by 5% flanking sequences of the FSH receptor gene that were transiently transfected into Sertoli cells were not down-regulated. In electrophoretic mobility shift assays (EMSA), cAMP-inducible nuclear protein complex containing c-Fos formed on the activator protein-1/cAMP responsive element-like site located at − 216 to − 210 in the promoter of the rat FSH receptor gene. We concluded from this study that there was no evidence for the putative role of ICER in the down-regulation of the FSH receptor promoter. In addition, the FSH-induced down-regulation of the transcription of the FSH receptor gene in Sertoli cells was prevented by the treatment of Sertoli cells with trichostatin A prior to the addition of FSH. This experiment coupled with other observations suggested that the down-regulation may be mediated by changes in chromatin structure.

The Id2 Transcriptional Repressor Is Induced by Follicle-stimulating Hormone and cAMP

“…In previous studies of Sertoli cells, overexpression of Id2 was found to repress E-box-mediated transcription from the promoters of the FSH receptor (2,8). Together, these observations suggest that FSH-induced sequestration of E-box factors by Id2 contributes to the decreases in endogenous FSH receptor RNA observed within 6 -8 h of FSH stimulation prior to the later restoration of FSH receptor mRNA to normal levels that has been reported previously (39,40). In vivo, the levels of FSH receptor on the Sertoli cell surface rise and fall in a cyclical manner, causing related changes in cAMP levels (13,41).…”

Sertoli Cell-specific Expression of Metastasis-associated Protein 2 (MTA2) Is Required for Transcriptional Regulation of the Follicle-stimulating Hormone Receptor (FSHR) Gene during Spermatogenesis

“…Desensitization of the FSH response in SCs involves multiple steps in signal transduction, among which the down-regulation of the transcription of the FSHR gene is of great importance (36). Previous study has shown that suppression of HADC activity by trichostatin A treatment completely prevents the homologous down-regulation of the transcription of the FSH receptor gene (26). Consistently, we have demonstrated that MTA2 represses FSH-mediated FSHR transcription by recruiting HDAC1.…”

“…The action of FSH during spermatogenesis is regulated at a fundamental level by controlling the number of competent receptors present at the surface of SCs. One mechanism of control is the down-regulation of the steady state levels of the FSHR gene after exposure to FSH by recruitment of HDAC (26). We observed that ablation of MTA2 expression significantly reversed the down-regulation of FSHR mRNA level by FSH treatment.…”

Orphan Receptor Chicken Ovalbumin Upstream Promoter Transcription Factors Inhibit Steroid Factor-1, Upstream Stimulatory Factor, and Activator Protein-1 Activation of Ovine Follicle-Stimulating Hormone Receptor Expression via Composite cis-Elements1

“…Although previous studies showed that SF-1 might contribute to cell-specific activity of mouse FSHR promoter [9], SF-1 alone may not be the sole mediator governing a Sertoli or granulosa cell-specific expression [19,47]. Additional elements and factors must synergize or antagonize SF-1 to direct the expression in a developmental manner [11,12,16]. In the present study, we showed that three activators of USF, AP-1, and SF-1 bound a composite ciselement (Figs.…”

“…In addition, different cellular combinations of transcription factors interact with the same promoter regions, leading to the type-specific transcription in the cells. Moreover, RNA processing and posttranslational modification also determine the functional protein levels of FSHR on the cell membrane [15,16]. Although some of the mechanisms by which the FSHR gene is down-regulated by FSH stimulation and protein kinase A signal transduction pathway have recently been proposed, little detailed information has been reported so far regarding the factors that lead to suppression of the FSHR gene [11,16].…”