Abstract
Brain mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respond to the same glucocorticoid hormones but can have differential effects on cellular function. Several lines of evidence suggest that MR‐specific target genes must exist and might underlie the distinct effects of the receptors. The present study aimed to identify MR‐specific target genes in the hippocampus, a brain region where MR and GR are co‐localised and play a role in the stress response. Using genome‐wide binding of both receptor types, we previously identified MR‐specific, MR‐GR overlapping and GR‐specific putative target genes. We now report altered gene expression levels of such genes in the hippocampus of forebrain MR knockout (fbMRKO) mice, killed at the time of their endogenous corticosterone peak. Of those genes associated with MR‐specific binding, the most robust effect was a 50% reduction in Jun dimerization protein 2 (Jdp2) mRNA levels in fbMRKO mice. Down‐regulation was also observed for the MR‐specific Nitric oxide synthase 1 adaptor protein (Nos1ap) and Suv3 like RNA helicase (Supv3 l1). Interestingly, the classical glucocorticoid target gene FK506 binding protein 5 (Fkbp5), which is associated with MR and GR chromatin binding, was expressed at substantially lower levels in fbMRKO mice. Subsequently, hippocampal Jdp2 was confirmed to be up‐regulated in a restraint stress model, posing Jdp2 as a bona fide MR target that is also responsive in an acute stress condition. Thus, we show that MR‐selective DNA binding can reveal functional regulation of genes and further identify distinct MR‐specific effector pathways.
Highlights
Endogenous glucocorticoid hormones affect brain function via two closely‐related nuclear receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR)
We identified Jdp[2] as a likely MR‐specific transcriptional target that is both down‐ regulated in forebrain MR knockout (fbMRKO) mice and up‐regulated in response to restraint stress
Nitric oxide synthase 1 adaptor protein (Nos1ap) and Supv[3] l1, two other genes linked to MR‐spe‐ cific binding sites, were expressed at a lower levels in fbMRKO mice but did not change upon restraint stress
Summary
Endogenous glucocorticoid hormones affect brain function via two closely‐related nuclear receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Several classical genomic MR‐targets have been described in various tissues over the past two decades, such as FK506 binding protein 5 (Fkbp5),[13] glucocorticoid‐induced leucine zipper (Gilz),[14] period circadian clock 1 (Per1)[15] and serum/glucocorticoid regulated kinase 1 (Sgk1).[16]. These genes are all known to be GR responsive as well.[17-20]. Transcriptional changes have been attributed to MR function,[23] they were not formally proven to be direct targets of the receptor and might be affected by MR activity in an indirect manner. NeuroD factors could coactivate glu‐ cocorticoid‐induced transactivation and were present near MR‐specific binding sites, suggesting that specific GRE‐dependent MR target genes do exist. Corticosterone responsiveness of Jdp[2], which is one of the genes with an MR‐bound promoter, was validated in mice that were exposed to different du‐ rations of restraint stress
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