Regulation of Gdnf expression by retinoic acid in Sertoli cells

Glial cell line‐derived neurotrophic factor (GDNF) and retinoic acid (RA) are two molecules crucial for the regulation of the spermatogonial compartment of the testis. During the cycle of the seminiferous epithelium, their relative concentration oscillates with lower GDNF levels in stages where RA levels are high. It has been recently shown that RA negatively regulates Gdnf expression but the mechanisms behind are so far unknown. Here, we show that RA directly downregulates Gdnf mRNA levels in primary murine Sertoli cells through binding of RARα to a novel DR5‐RARE on Gdnf promoter. Pharmacological inhibition and chromatin immunoprecipitation–quantitative polymerase chain reaction analysis suggested that the underlying mechanism involved histone deacetylase activity and epigenetic repression of Gdnf promoter upon RA treatment. Retinoic acid (RA) and Glial cell line‐derived neurotrophic factor (GDNF) are two main players of the spermatogonial compartment whose concentration varies cyclically during the cycle of the seminiferous epithelium. Here we show that RA‐dependent Gdnf downregulation involves the binding of RARα to a novel identified DR5‐RARE binding site on murine Gdnf promoter and epigenetic repression of Gdnf expression levels.