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

Abstract

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 ␣ or ␤ estrogen receptors (ER␣ or ER␤, respectively). The results demonstrate that estradiol (E 2 ) increases the activity of the hUcn promoter via ER␣, and decreases hUcn promoter activity through ER␤. Deletions of the hUcn promoter show that the increase in promoter activity mediated by E 2 -ER␣ depends on a promoter region containing a half-estrogen response element and an Sp1 site, and the decrease mediated by E 2 -ER␤ 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.

Increased Hippocampal Expression of the Divalent Metal Transporter 1 (DMT1) mRNA Variants 1B and +IRE and DMT1 Protein After NMDA-Receptor Stimulation or Spatial Memory Training

“…Cells were subsequently incubated with Alexa Fluor Ò 488 anti-rabbit or Alexa Fluor Ò 635 anti-mouse as secondary antibody. Brain tissue fixation and immunohistochemistry were performed as described (Haeger et al 2006), except that coronal slices were incubated at 4°C overnight with PanDMT1 and MAP2 antibodies. Sections were incubated at room temperature for 2 h in PBS buffer containing 0.2% gelatin and 0.1% Triton X-100 plus the Alexa antibodies defined above, rinsed in PBS, and mounted with glycerol.…”

Estrogen Disrupts the Inhibition of Fear in Female Rats, Possibly through the Antagonistic Effects of Estrogen Receptor α (ERα) and ERβ

“…Moreover, ER␣ activates and ER␤ inhibits many of the same gene targets. For example, ER␣ activates and ER␤ inhibits gene transcription at the AP1 response element (Paech et al, 1997), and ER␣ enhances activity whereas ER␤ reduces activity in the promoter region of the urocortin receptor gene (Haeger et al, 2006). It has been found that ER␤ forms heterodimers with ER␣ and acts to repress the activational effects of ER␣ on gene expression (Hall and McDonnell, 1999).…”

Enhanced pelvic responses to stressors in female CRF-overexpressing mice

“…It is well documented that women under stress conditions develop functional diseases such as IBS (24), IC (55), and comorbid disorders (6,78) with anxiety more prevalently than men. Whether estrogen receptors, known to influence the activity of the CRF promoter and transcriptional activity of the urocortin gene (18,69), play a role in this sex difference warrants investigation.…”