An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH-Like activity in gonadotropin-deficient transgenic mice

FSH mediates its testicular actions via a specific Sertoli cell G protein-coupled receptor. We created a novel transgenic model to investigate a mutant human FSH receptor (FSHR+) containing a single amino acid substitution (Asp567Gly) equivalent to activating mutations in related glycoprotein hormone receptors. To examine the ligand-independent gonadal actions of FSHR+, the rat androgen-binding protein gene promoter was used to direct FSHR+ transgene expression to Sertoli cells of gonadotropin-deficient hypogonadal (hpg) mice. Both normal and hpg mouse testes expressed FSHR+ mRNA. Testis weights of transgenic FSHR+ hpg mice were increased approximately 2-fold relative to hpg controls (P < 0.02) and contained mature Sertoli cells and postmeiotic germ cells absent in controls, revealing FSHR+-initiated autonomous FSH-like testicular activity. Isolated transgenic Sertoli cells had significantly higher basal (similar to2-fold) and FSH-stimulated (similar to50%) cAMP levels compared with controls, demonstrating constitutive signaling and cell-surface expression of FSHR+, respectively. Transgenic FSHR+ also elevated testosterone production in hpg testes, in the absence of circulating LH (or FSH), and it was not expressed functionally on steroidogenic cells, suggesting a paracrine effect mediated by Sertoli cells. The FSHR+ response was additive with a maximal testosterone dose on hpg testicular development, demonstrating FSHR+ activity independent of androgen-specific actions. The FSHR+ response was male specific as ovarian expression of FSHR+ had no effect on hpg ovary size. These findings reveal transgenic FSHR+ stimulated a constitutive FSH-like Sertoli cell response in gonadotropin-deficient testes, and pathways that induced LH-independent testicular steroidogenesis. This novel transgenic paradigm provides a unique approach to investigate the in vivo actions of mutated activating gonadotropin receptors.