Glucocorticoid receptor isoform‐specific regulation of development, circadian rhythm, and inflammation in mice

Abstract

Glucocorticoids are primary stress hormones, and their synthetic derivatives are widely used clinically. The therapeutic efficacy of these steroids is limited by side effects and glucocorticoid resistance. Multiple glucocorticoid receptor (GR) isoforms are produced from a single gene by alternative translation initiation; however, the role individual isoforms play in tissue-specific responses to glucocorticoids is unknown. We have generated knockin mice that exclusively express the most active receptor isoform, GR-C3. GR-C3 knockin mice die at birth due to respiratory distress. Microarray analysis of fibroblasts from wild-type and GR-C3 mice indicated that most genes regulated by GR-C3 were unique to this isoform. Antenatal glucocorticoid administration rescued GR-C3 knockin mice from neonatal death. Dual-energy X-ray absorptiometry revealed no major alterations in body composition for rescued knockin mice. Rescued female, but not male, GR-C3 mice exhibited increased wheel running activity in the light portion of the day. LPS administration induced premature mortality in rescued GR-C3 knockin mice, and gene expression studies revealed a deficiency in the ability of GR-C3 to repress a large cohort of immune and inflammatory response genes. These findings demonstrate that specific GR translational isoforms can influence development, circadian rhythm, and inflammation through the regulation of distinct gene networks.-Oakley, R. H., Ramamoorthy, S., Foley, J. F., Busada, J. T., Lu, N. Z., Cidlowski, J. A. Glucocorticoid receptor isoform-specific regulation of development, circadian rhythm, and inflammation in mice.

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…ago (similarly to NF-κB) from sequential duplications of two ancestral genes, those of the estrogen and the glucocorticoid receptors; the latter ultimately evolved into the glucocorticoid and the mineralocorticoid receptors (67,71). Underlying its essential role in formation and regulation of multicellular life, the GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions (72) while GRs are vital for the structural and functional maturation of fetal organs (73,74), affecting almost 4,000 genes (75). In late gestation of mammals, fetal glucocorticoid levels rise dramatically, an essential step for maturation in preparation for life after birth.…”

“…Notably, 16 variants of the human GR (hGR) have been identified to date with the potential of at least 256 combinations of homo-and hetero-dimers (68). Recent research indicates that the expression of different GR transcriptional and translational isoforms might be a significant factor determining how GCs influence the biological function and activity of specific cells and tissues (75). In contrast to GRα, the alternatively transcribed GRβ, which resides primarily in the cell nucleus, does not bind glucocorticoid, but can form homodimers with itself or heterodimers with a GRα subtype, functioning as an antagonist of GRα.…”

Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor

“…The lethality of these mice could be overcome by antenatal GC administration, and adult mice were hypersensitive to LPS administration. This indicated that either the absence of other isoforms like the most abundant GR-A, or indeed the specific overexpression of GR-C3 might confer anti-inflammatory actions [(142); Figure 4E]. However, further studies are warranted to dissect these observations in more detail.…”

Corticosteroid Receptors in the Brain: Transcriptional Mechanisms for Specificity and Context-Dependent Effects

“…This domain is important in that it contains the AF-1 region that is able to stimulate transcription even in the absence of ligand. Of note, the N-terminal domain can differ in length, as a consequence of alternative translation initiation (Lu and Cidlowski 2005 ; Viengchareun et al 2007 ), and these translation variants may differ in their activities (Wu et al 2013 ; Oakley et al 2018 ). Because it is difficult to distinguish between these protein variants in vivo (other than with antibodies that recognize the actual N-terminus), their relevance for brain function remains largely unknown.…”