Regulation of Sertoli-Germ Cell Adhesion and Sperm Release by FSH and Nonclassical Testosterone Signaling

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2011-02, Vol.25 (2), p.238-252
• Main Authors: Shupe, John, Cheng, Jing, Puri, Pawan, Kostereva, Nataliya, Walker, William H
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Follicle Stimulating Hormone - metabolism; Male; Original Research; Phosphorylation; Promoter Regions, Genetic - genetics; raf Kinases - metabolism; Rats; Seminiferous Tubules; Sertoli Cells - physiology; Signal Transduction; Spermatogenesis; Spermatozoa - physiology; src-Family Kinases - metabolism; Testosterone - genetics; Testosterone - metabolism
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2010-0030

FSH and testosterone regulate processes required for spermatogenesis and male fertility via a non-classical testosterone signaling pathway in Sertoli cells. Testosterone and FSH act in synergy to produce the factors required to maximize the production of spermatozoa and male fertility. However, the molecular mechanisms by which these hormones support spermatogenesis are not well established. Recently, we identified a nonclassical mechanism of testosterone signaling in cultured rat Sertoli cells. We found that testosterone binding to the androgen receptor recruits and activates Src tyrosine kinase. Src then causes the activation of the epidermal growth factor receptor, which results in the phosphorylation and activation of the ERK MAPK and the cAMP response element-binding protein transcription factor. In this report, we find that FSH inhibits testosterone-mediated activation of ERK and the MAPK pathway in Sertoli cells via the protein kinase A-mediated inhibition of Raf kinase. In addition, FSH, as well as inhibitors of Src and ERK kinase activity, reduced germ cell attachment to Sertoli cells in culture. Using pathway-specific androgen receptor mutants we found that the nonclassical pathway is required for testosterone-mediated increases in germ cell attachment to Sertoli cells. Studies of seminiferous tubule explants determined that Src kinase, but not ERK kinase, activity is required for the release of sperm from seminiferous tubule explants. These findings suggest the nonclassical testosterone-signaling pathway acts via Src and ERK kinases to facilitate the adhesion of immature germ cells to Sertoli cells and through Src to permit the release of mature spermatozoa. In contrast, FSH acts to limit testosterone-mediated ERK kinase activity and germ cell attachment.