Nociceptin is upregulated by FSH signaling in Sertoli cells in murine testes

► Nociceptin is traditionally known as a neuropeptide. ► Phosphorylated CREB associates with prepronociceptin gene encoding nociceptin. ► FSH signaling induces prepronociceptin mRNA in Sertoli cells. ► FSH signaling upregulates the nociceptin peptide in Sertoli cells. ► FSH surge follows the nociceptin peptide production in testes after 9dpp. In postnatal testes, follicle-stimulating hormone (FSH) acts on somatic Sertoli cells to activate gene expression directly via an intracellular signaling pathway composed of cAMP, cAMP-dependent protein kinase (PKA), and cAMP-response element-binding protein (CREB), and promotes germ cell development indirectly. Yet, the paracrine factors mediating the FSH effects to germ cells remained elusive. Here we show that nociceptin, known as a neuropeptide, is upregulated by FSH through cAMP/PKA/CREB pathway in Sertoli cells in murine testes. Chromatin immunoprecipitation from Sertoli cells shows that CREB phosphorylated at Ser133 associates with prepronociceptin gene encoding nociceptin. Analyses with Sertoli cells and testes demonstrates that both prepronociceptin mRNA and the nociceptin peptide are induced after FSH signaling is activated. In addition, the nociceptin peptide is induced in testes after 9days post partum following FSH surge. Thus, our findings may identify nociceptin as a novel paracrine mediator of the FSH effects in the regulation of spermatogenesis.