Sertoli Cell-Derived GDNF is Necessary for Quantitively Normal Spermatogenesis in Adult Mice

In mammalian testes, spermatogenesis continually produces numerous spermatozoa dependent on the activity of spermatogonial stem cells (SSCs). Balance between self-renewal and differentiation fate decision by SSCs is necessary for maintaining the normal spermatogenesis and male fertility presumably occurs in response to external signal emanating from the niche such as Glial cell-lined derived neurotrophic factor (GDNF) that promotes SSC survival and self-renewal. For many years, it was considered that this GDNF was only produced by Sertoli cells. This idea was challenged recently by experiment demonstrating that production of GDNF by peritubular myoid (PM) cells is also essential for normal spermatogenesis. Surprisingly, though the hypothesis that in vivo production of GDNF by Sertoli cells is required for normal spermatogenesis, had never been tested. Therefore, we sought to address this hypothesis through conditional deletion of Gdnf in Sertoli cells of adult testes using tamoxifen-inducible Cre/lox genetics. Adult mice bearing a Sox9-CreERT2 transgene, a Rosa26-LacZ Cre reporter and with the following genotypes, Gdnf +/+, Gdnf fl/+ or Gdnf fl/fl were treated with tamoxifen to induce Sertoli cell-specific Gdnf deletion. Breeding studies showed that the fecundity of Gdnf Sertoli cell cKO mice was significantly lower (1.84 +/-0.46/litter) than controls (wild-type and Gdnf Sertoli cell cHet; 4.22+/-0.55 /litter; p ≤ 0.0012). In addition, testes weight of Gdnf Sertoli cell cKO mice was significantly lower (77.1 +/-7.46 mg) than controls (104.7+/-7.96 mg; p ≤ 0.017). Cre reporter (LacZ) expression and genotyping studies confirmed Cre-recombination and presence of floxed deleted Gdnf allele in cKO and cHet mice, respectively.