Estrogen Receptors α and β Differentially Regulate the Transcriptional Activity of the Urocortin Gene

Urocortin (Ucn), a highly conserved metazoan gene, is related to stress and feeding, behaviors with significant gender differences. We investigated whether estrogens regulate the expression of the Ucn gene using transient transfection in PC12 cells with the human Ucn (hUcn) promoter coupled to luciferase and either α or β estrogen receptors (ERα or ERβ, respectively). The results demonstrate that estradiol (E 2 ) increases the activity of the hUcn promoter via ERα, and decreases hUcn promoter activity through ERβ. Deletions of the hUcn promoter show that the increase in promoter activity mediated by E 2 -ERα depends on a promoter region containing a half-estrogen response element and an Sp1 site, and the decrease mediated by E 2 -ERβ depends on a proximal promoter region containing a cAMP response element. Ucn and ERs coexist in neurons of rat hypothalamic nuclei, giving anatomical support for a direct effect of estrogen receptors on the Ucn gene. By in situ hybridization, we observed that cycling female rats have a higher number of cells expressing Ucn mRNA than males in the paraventricular nucleus of the hypothalamus (PVN) and the septum. Both of these brain nuclei are related to stress behaviors and express moderate levels of Ucn. Furthermore, Ucn mRNA was significantly decreased in the PVN and increased in the septum 30 d after ovariectomy. Acute E 2 administration to ovariectomized rats significantly increased Ucn mRNA expression in the PVN and septum. In conclusion, our in vitro and in vivo evidence suggests that estrogens exert a direct and differential transcriptional regulation of the Ucn gene.