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Submitted on January 22, 2002
Accepted on July 24, 2002
1 Andrology Laboratory (M.H., N.T., J.S., A.K., M.J., D.J.H., C.M.A), ANZAC Research Institute, Sydney NSW 2139, Australia; Institute of Reproductive Medicine (J.G., M.S., V.N.), University of Münster, D-48419 Münster, Germany.
* To whom correspondence should be addressed. E-mail: charles{at}med.usyd.edu.au.
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 gonadotrophin-deficient hypogonadal (hpg) mice. Both normal and hpg mouse testes expressed FSHR+ mRNA. Testis weights of transgenic-FSHR+ hpg mice were increased 
2-fold relative to hpg controls (P < 0.02), and contained mature Sertoli cells and post-meiotic germ cells absent in controls, revealing FSHR+ initiated autonomous FSH-like testicular activity. Isolated transgenic Sertoli cells had significantly higher basal (2-fold) and FSH-stimulated (50%) 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), nor was it 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 gonadotrophin-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 gonadotrophin receptors.
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