FSH-stimulated PTEN activity accounts for the lack of FSH mitogenic effect in prepubertal rat Sertoli cells

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 20A c c e p t e d M a n u s c r i p t ABSTRACT Follicle-stimulating hormone (FSH) controls the proliferation and differentiation of Sertoli cells of the testis. FSH binds a G protein-coupled receptor (GPCR) to stimulate downstream effectors of the phosphoinositide-3 kinase (PI3K)-dependent pathway, without enhancing PI3K activity. To clarify this paradox, we explored the activity of phosphatase and tensin homolog deleted in chromosome 10 (PTEN), the PI3K major regulator, in primary cultures of rat Sertoli cells. We show that, within minutes, FSH increases PTEN neosynthesis, requiring the proteasomal degradation of an unidentified intermediate, as well as PTEN enzymatic activity. Importantly, introducing an antisense cDNA of PTEN into differentiating Sertoli cells restores FSHdependent cell proliferation. In conclusion, these results provide a new mechanism of PTEN regulation, which could serve to block entry into S phase of Sertoli cells, while they are proceeding through differentiation in pre-pubertal animals.

Age-dependent expression of Pten and Smad4 genes in the urogenital system of Wistar rats

“…Acute stimulation of rat testicular Sertoli cells, required for male sexual development, by FSH has been found to increase Pten synthesis and enzymatic activity, thus identifying a new, Pten-dependent mechanism of regulating spermatogenesis 11 . In rats, FSH plasma levels peak between 10 and 15 weeks and decline after this period 12 , which agrees with our findings that, in rat testes, Pten expression increased with maturation from the pre-pubertal (21 days) to the young adult (90 days) stage, but then decreased in the older, middle-aged (180 days) group.…”

Effects of the IGF-1/PTEN/Akt/FoxO signaling pathway on male reproduction in rats subjected to water immersion and restraint stress

“…Wu et al demonstrated that PTEN may have a role in the late period of sperm development (18). Dupont et al (19) treated mice with exogenous FSH and estrogen, and reported that FSH controls proliferation and differentiation of Sertoli cells via stimulation of PTEN activity. Moe-Behrens et al (37) reported estrogen exposure induced formation of germ cell testicular tumors via the Akt/PTEN signaling pathway.…”

“…Wu et al hypothesized that PTEN may have a role in the late stage of sperm development (18). Dupont et al demonstrated that estrogen induced testicular tumors in mice via the PTEN/Akt signal pathway (19). Similarly, Kimura et al revealed that PTEN gene knockout could lead to testicular tumors in mice (20).…”

Mapping the follicle-stimulating hormone-induced signaling networks

“…FSH has been shown to lead to PI3K activation, PIP3 accumulation, and FSH-dependent proliferation in both granulosa cells and primary Sertoli cells from newborn rat (Park et al, 2005; Musnier et al, 2009; Dupont et al, 2010). Interestingly, in differentiating rat Sertoli cells, PIP3 accumulation is negatively regulated by PTEN whose expression is strongly and rapidly induced upon FSH stimulation, which results in a blockade of FSH-induced proliferation (Dupont et al, 2010). …”