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 ( approximately 2-fold) and FSH-stimulated ( approximately 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), 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.
Haywood
Miriam
M
Andrology Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
Tymchenko
Nina
N
Spaliviero
Jenny
J
Koch
Adam
A
Jimenez
Mark
M
Gromoll
Jörg
J
Simoni
Manuela
M
Nordhoff
Verena
V
Handelsman
David J
DJ
Allan
Charles M
CM
D019943:Amino Acid Substitution; D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid; D002478:Cells, Cultured; D005091:Exons; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D005998:Glycine; D006062:Gonadotropins / Q000172:deficiency*; D006801:Humans; D007438:Introns; D007985:Leydig Cells / Q000166:cytology / Q000502:physiology; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D051381:Rats; D011962:Receptors, FSH / Q000502:physiology*; D012708:Sertoli Cells / Q000166:cytology / Q000502:physiology; D013737:Testis / Q000166:cytology / Q000502:physiology
D000727:Androgen-Binding Protein; D006062:Gonadotropins; D011962:Receptors, FSH; D001224:Aspartic Acid; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D005998:Glycine