ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: PLoS One. 2019; 14(12): e0226753. PMID: 31869387.

Glucocorticoids (cortisol in humans, corticosterone in most rodents) are steroid hormones secreted by the adrenal cortex into the systemic circulation in an ultradian, circadian, and stress-related fashion under the control of the hypothalamic-pituitary-adrenal (HPA) axis. These cholesterol-derived molecules participate in the physiologic function of almost all organs and play an important role in the maintenance of resting and stress-related homeostasis (1, 2). At the cellular level, the actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), which is encoded by the NR3C1 gene and belongs to the steroid/thyroid/retinoic acid nuclear receptor superfamily of transcription factors (3, 4). Consistent with the pleiotropic effects of glucocorticoids, the hGR is ubiquitously expressed in all human tissues and cells and is necessary for life after birth (5). GR functions as a ligand-activated transcription factor that influences the transcription rate of numerous genes through well-described genomic and less well-defined nongenomic actions (3-5). GR regulates gene expression by either transcriptional activation (transactivation) or transcriptional repression (transrepression). Prior to binding to glucocorticoids, the hGR resides mostly in the cytoplasm of cells as part of a large multiprotein complex. Upon ligand-induced activation, the GR undergoes conformational changes that result in dissociation from this multiprotein complex and translocation into the nucleus, where it binds to glucocorticoid-response elements (GREs) in the promoter region of target genes. The ligand-activated GR can also modulate gene expression independently of DNA-binding, by interacting with other transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), p53 and signal transducers and activators of transcription (STATs) (3, 4).

In this study, the authors created GR^dim/dim mutant mice with a point mutation (A458T) in the DNA binding domain (DBD) of the GR, in which GR dimerization is impaired and DNA binding is less robust, however, the monomeric GR functions remain intact. Subsequently, the authors evaluated the effect of poor GR dimerization on hippocampus-dependent cognition, as well as on exploration and emotional behavior under baseline and chronically increased stress hormone levels. Thus, they analyzed the behavioral phenotype of female GR^dim/dim mice under baseline and under chronically elevated corticosterone levels compared with their wild-type littermates. Specifically, they compared behavior spanning general activity, emotional behavior and cognitive performance under these two conditions. In addition, they analysed expression levels of selected genes that have been shown to be differentially regulated by i) corticosterone and stress, (ii) in major depressive disorders in the hippocampus, and (iii) play an important role in cognitive processes especially in learning impairments reported in preclinical models and clinical population of depression. They found that GR^dim/dim mice did not behave differently from GR^wt/wt littermates under baseline conditions. However, after chronic elevation of stress hormone levels, GR^dim/dim mice displayed impaired hippocampus-dependent memory compared to GR^wt/wt mice, which correlated with differential expression of hippocampal Bdnf/TrkB and Fkbp5. These data suggest that the phenotypic problem in maintaining a good memory after chronic stress in GR^dim/dim mice is not reflected in the lack of repression of these genes in the hippocampus, and it may be that other genes, not tested here or as yet not recognized, are regulated by GR dimers in this specific control.

References:

1. Nicolaides NC, Charmandari E, Kino T, Chrousos GP. Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health. Front Endocrinol (Lausanne). 2017; 8:70.

2. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005; 67: 259–84.

3. Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010; 75(1): 1–12.

4. Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids. 2005; 70: 407–417.

5. Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schütz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 1995; 9: 1608–1621.