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Identification of mineralocorticoid receptor target genes in the mouse hippocampus
Author(s) -
van Weert Lisa T. C. M.,
Buurstede Jacobus C.,
Sips Hetty C. M.,
Vettorazzi Sabine,
Mol Isabel M.,
Hartmann Jakob,
Prekovic Stefan,
Zwart Wilbert,
Schmidt Mathias V.,
Roozendaal Benno,
Tuckermann Jan P.,
Sarabdjitsingh R. Angela,
Meijer Onno C.
Publication year - 2019
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12735
Subject(s) - glucocorticoid receptor , mineralocorticoid receptor , biology , endocrinology , medicine , receptor , forebrain , mineralocorticoid , gene , hippocampal formation , glucocorticoid , hippocampus , microbiology and biotechnology , genetics , central nervous system
Brain mineralocorticoid receptors ( MR s) and glucocorticoid receptors ( GR s) 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 (fb MRKO ) 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 fb MRKO 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 FK 506 binding protein 5 ( Fkbp5 ), which is associated with MR and GR chromatin binding, was expressed at substantially lower levels in fb MRKO 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.