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A developmental shift in glucocorticoid receptor expression preserves glucocorticoid sensitivity in the adult suprachiasmatic nucleus.

ABSTRACT: The circadian system synchronizes physiology, improving the adaptation to daily environmental changes. In mammals, the master pacemaker, in the suprachiasmatic nuclei (SCN) of the hypothalamus, coordinates “wake” functions by inducing the circadian release of glucocorticoids (GCs). GCs entrain the clocks of a wide variety of tissues through GC receptor (GR) activation, however, the influence of GCs on the SCN is unclear and seems to depend on the maturity of the circuit. During the perinatal period, the mouse SCN express GR and respond directly to GCs while the adult SCN express low GR and have been traditionally considered resistant to GCs. To understand the change of sensitivity to GCs we followed the developmental trajectory of the mouse SCN, and found that while GR is expressed in all SCN cells early in life it remains expressed mainly in astrocytes in the adult. Using a model of prenatal exposure to GCs we found that offspring from treated mothers, adapt slower to shifted light-dark cycle and shows reduced expression of GR in SCN astrocytes. The adult SCN astrocytes can indeed sense and respond to GCs with rapid astrocytic Ca2+ events that propagate across neighboring cells, an effect that is prevented by the specific inhibition of astrocyte-astrocyte communication. Our findings provide a conceptual advance on how the mouse clock develops and on the influence that GCs have on the SCN. This might be relevant to understand how circadian synchrony is restored in conditions of temporal misalignment, such as jet lag.

ORGANISM(S): Mus musculus

PROVIDER: GSE240803 | GEO | 2024/04/10

REPOSITORIES: GEO

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Project description:Glucocorticoids (GCs) are among the most effective and frequently prescribed anti-inflammatory drugs in dermatology. The effects of GCs are mediated by the glucocorticoid receptor (GR), a well-known transcription factor (TF). Despite the well-studied therapeutic and adverse effects of GCs, the molecular signature of GC/GR in human skin is largely unknown. Here, we present a bioinformatics analysis of the human skin transcriptome induced by the glucocorticoid clobetasol propionate (CBP). Full thickness arm skin biopsies were obtained from a cohort of 17 healthy volunteers balanced in sex and race (African-American and Caucasian) 24 hrs after single CBP topical application. Non-treated skin from the same volunteers served as control. Analyses of differentially expressed genes (DEGs) and gene set enrichments (GSE) from RNASeq reflected anti-inflammatory, metabolic and atrophogenic effects of GCs in skin. More than 40% of all DEGs were non-coding RNAs, including long non-coding RNAs (lncRNAs) suggesting that GR effects in skin may extend towards regulation at the post-transcriptional level. Furthermore, we observed sexual and racial dimorphism in the CBP response including a shift towards IFNg/IFNa and IL6/JAK/STAT3 signaling in female skin; and an overall larger response to CBP (increased number of DEGs and increased induction of some GR-target genes) in African-American skin. Weighted gene co-expression network analysis (WGCNA) unveiled a regulatory network comprising 41 TFs, with network hub TFs enriched for direct GR targets and ~ 260 of their target genes that were enriched for the majority of altered functional pathways of the entire CBP transcriptome. Interestingly, ~ 80% of these TFs involved in the regulation of circadian clock, metabolism, and development have been associated with skin aging supporting at the molecular level the known similarities between skin chronically treated with GCs and aged skin. Overall, these findings indicate that GR acts as a master regulator of gene expression in skin via multiple mechanisms including regulation of expression of noncoding RNAs and multiple core TFs

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A developmental shift in glucocorticoid receptor expression preserves glucocorticoid sensitivity in the adult suprachiasmatic nucleus.

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