The Expression of the Follicle-stimulating Hormone Receptor in Spermatogenesis

Abstract

Results from experiments using mouse models suggest that the role of follicle-stimulating hormone (FSH) in spermatogenesis is the regulation of Sertoli cell proliferation and, ultimately, the size and spermatogenic capacity of the testis. The regulation of the expression of the FSH receptor (FSHR) gene is very cell specific and plays an initial role in the ultimate response of the Sertoli cells to FSH. The extreme cell specificity and the importance of the FSH response to spermatogenesis have led to an extensive characterization of the promoter of the FSHR gene. Several widely expressed transcription factors -including USF 1 and 2, GATA-1, and SF-1 and potential elements such as an E2F site and an Inr region -have been shown to contribute to the maximal transcription of the transfected FSHR gene. However, these experiments have failed to provide clues as to the cell-specific expression of the FSHR gene. In both cell transfections and in transgenic mice, the promoter can direct expression of transgenes promiscuously. The rodent FSHR promoter contains conserved CpG dinucleotides that were shown to be methylated in nonexpressing cells and tissue but unmethylated in Sertoli cells. The methylated CpG sites could interfere with the binding of general transcription factors and/or lead to a repressive chromatin structure in the nonexpressing cells. While yet-undiscovered cell-specific factors may play a role in the expression of the FSHR gene, repression and activation of local chromatin structure are likely to be involved. I. Biology of the Follicle-stimulating Hormone (FSH) Receptor in SpermatogenesisThe primary hormonal controls on spermatogenesis involve the action of FSH and testosterone on Sertoli cells. Many of the studies examining the actions of FSH have been done on cultured Sertoli cells from 10-to 30-day-old rats. The Sertoli cells from rats of this age are easily placed in culture and respond to FSH with increased levels of cyclic AMP (cAMP), increased protein synthesis, and increased estradiol production (Fritz et al., 1976). As the age of the rat increases to 40 days or more, the response of Sertoli cells both in culture and in vivo changes. There is a large increase in the phosphodiesterase activity in the cells and the accumulation of cAMP and the subsequent stimulation of specific protein 129

A close correlation in the expression patterns of Af-6 and Usp9x in Sertoli and granulosa cells of mouse testis and ovary

“…It is well known that FSH plays a key role in the control and maintenance of normal gametogenesis through Sertoli cells (Nieschlag et al 1999, Heckert & Griswold 2002 or ovarian granulosa cells (Gromoll et al 1996, O'Shaughnessy et al 1996. Most interestingly, in this study, to accompany an increase of Af-6 expression, Usp9x was also found to be synchronously up-regulated in granulosa cells of the late-secondary and Graafian follicles in the ovaries treated with PMSG.…”

Regulation of Male Fertility by the Opioid System

“…In contrast, the LH receptor is expressed mainly in Leydig cells but is also mildly expressed in spermatogenic cells (22,23). The main function of FSH is to stimulate the proliferation of Sertoli cells during puberty, whereas LH regulates the synthesis of testosterone in the adult testes (24). Administration of morphine is associated with a suppression of LH release, whereas opioid antagonists such as naloxone and naltrexone produce increased serum levels of LH in humans and many animal species (25,26).…”

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

“…To bypass these effects, which would preclude adjudin from being developed into a male contraceptive for human use, this drug would have to be delivered directly to the testis. To achieve this, adjudin was conjugated to a recombinant FSH mutant protein, which served as its "carrier" to the testis , because FSH receptors are restricted to Sertoli cells in the testis (Heckert and Griswold, 2002;Walker and Cheng, 2005;Hermann and Heckert, 2007) (Fig. 11).…”