Nociceptin induces Rec8 phosphorylation and meiosis in postnatal murine testes.

Phosphorylated Rec8, a key component of cohesin, mediates the association and disassociation, "dynamics," of chromosomes occurring in synaptonemal complex formation, crossover recombination, and sister chromatid cohesion during meiosis. Yet, the extrinsic factors triggering meiotic chromosome dynamics remain elusive. We have recently found that nociceptin, known as a neuropeptide, is up-regulated by follicle-stimulating hormone in Sertoli cells in postnatal murine testes; however, very little is known about the functional role of nociceptin in spermatogenesis. Here, we show that nociceptin induces Rec8 phosphorylation, triggering chromosome dynamics, in spermatocytes during meiosis in postnatal murine testes. The nociceptin receptor Oprl-1 is exclusively expressed in the plasma membrane of testicular germ cells, mostly spermatocytes. Treatment of testes with nociceptin resulted in a rapid phosphorylation of Rec8. Injection of nociceptin into mice stimulated Rec8 phosphorylation and meiotic chromosome dynamics in testes, whereas injection of nocistatin, a specific inhibitor of nociceptin, abolished them. These findings suggest that nociceptin is a novel extrinsic factor that plays a crucial role in the progress of meiosis.

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

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.