MicroRNA 18 and 124a Down-Regulate the Glucocorticoid Receptor: Implications for Glucocorticoid Responsiveness in the Brain

Abstract

Glucocorticoids (GCs) exert profound effects on a variety of physiological processes, including adaptation to stress, metabolism, immunity, and neuronal development. Cellular responsiveness to GCs depends on numerous factors, including the amount of the glucocorticoid receptor (GR) protein. We tested the hypothesis that micro-RNAs (miRs), a recently discovered group of noncoding RNAs involved in mRNA translation, might control GR activity by reducing GR protein levels in neuronal tissues. We tested a panel of five miRs consisting of 124aa, 328, 524, 22, and 18. We found that miRs 18 and 124a reduced GR-mediated events in addition to decreasing GR protein levels. miR reporter assays revealed binding of miR-124a to the 3' untranslated region of GR. In correspondence, the activation of the GR-responsive gene glucocorticoid-induced leucine zipper was strongly impaired by miR-124a and -18 overexpression. Although miR-18 is expressed widely throughout the body, expression of miR-124a is restricted to the brain. Endogenous miR-124a up-regulation during neuronal differentiation of P19 cells was associated with a decreasing amount of GR protein levels and reduced activity of luciferase reporter constructs bearing GR 3' untranslated regions. Furthermore, we show that miR-124a expression varies over time during the stress hyporesponsive period, a neonatal period when GC signaling is modulated. Our findings demonstrate a potential role for miRs in the regulation of cell type-specific responsiveness to GCs, as may occur during critical periods of neuronal development. Ultimately, our results may provide a better understanding of the etiology of stress-related diseases as well as the efficacy of GC therapy.

Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice

“…Another level of fine-tuning GR levels can be provided by miRs, by directing mRNA destabilization and translational repression (91). Recently, it was reported that miR18 and miR124a reduce GR expression, which leads to impairment of the transcriptional response of GR (92). Therefore, TNF␣ might induce the expression of GR down-regulating miRs.…”

Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more

“…In contrast to 1 miR-18, which was expressed in numerous tissues, miR-124a expression was restricted to 2 certain brain regions and changed during the stress neonatal hyporesponsive period [85]. 3…”

Molecular and Epigenetic Mechanisms Underlying Cognitive and Adaptive Responses to Stress

“…We found that forced swimming results in increased DNA methylation of the Nr3c1 gene associated with an enhanced binding of DNMT3A, which may explain the reduction in gene expression after stress. Furthermore, as it has previously been shown that the microRNA mir-124a can reduce GR mRNA expression in vitro [60], we investigated the expression of this microRNA under baseline conditions and after FS stress in vivo. Forced swimming indeed evoked a significantly increased expression of mir124a in the DG, which was negatively correlated with the expression of GR mRNA expression.…”