Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

Abstract

Adaptation to stress in vertebrates occurs via activation of hormonal and neuronal signaling cascades in which corticotropinreleasing hormone (CRH) plays a central role. Expression of brain CRH is subject to strong, brain-region specific regulation by glucocorticoid hormones and neurogenic intracellular signals. We hypothesized that Steroid Receptor Coactivator 1 (SRC-1), a transcriptional coregulator of the glucocorticoid receptor, is involved in the sensitivity of CRH regulation by stress-related factors. In the brains of SRC-1 knockout mice we found basal CRH mRNA levels to be lower in the central nucleus of the amygdala. Hypothalamic CRH up-regulation after chronic (but not acute) stress, as well as region-dependent up-and down-regulation induced by synthetic glucocorticoids, were significantly attenuated compared with wild type. The impaired induction of the crh gene by neurogenic signals was corroborated in AtT-20 cells, where siRNA and overexpression experiments showed that SRC-1 is necessary for full induction of a CRH promoter reporter gene by forskolin, suggestive of involvement of transcription factor CREB. In conclusion, SRC-1 is involved in positive and negative regulation of the crh gene, and an important factor for the adaptive capacity of stress.adaptation ͉ amygdala ͉ HPA axis ͉ neuroendocrinology ͉ transcription B rain corticotropin-releasing hormone (CRH) plays a pivotal role in the mammalian response to stress. CRH synthesized by neurons in the central nucleus of the amygdala (CeA) mediates the effect of stress on emotional states, including fear and anxiety (1, 2). From the paraventricular nucleus of the hypothalamus (PVN) CRH coordinates autonomic outflow and the activity of the hypothalamus-pituitary-adrenal (HPA) axis. The latter leads to secretion of the adrenal glucocorticoid hormones, which in turn orchestrate the adaptation to stress of virtually all tissues in the body (3-5).As part of adaptation, CRH expression itself is strongly regulated in response to stress-induced elevations of glucocorticoids and neurogenic signals. In the core of the HPA-axis, activation of the glucocorticoid receptor (GR) can repress transcription from the crh gene as part of negative feedback, whereas stress-related noradrenergic and glutamatergic excitatory signals can activate the gene, in part via activation of the transcription factor CREB. In the CeA, both GR activation and excitatory signals can lead to an increased CRH expression (6, 7). These modulations are considered crucial for stress adaptation, and a considerable amount of research has been devoted to understand how transcriptional signals are integrated at the level of the CRH promoter, both in vitro and in vivo (8, 9). Nevertheless, the regulation of the crh gene in vivo is far from understood.Transcriptional coregulators constitute an expanding class of molecules that act as mediators and integrators of signals carried by nuclear receptors, such as GR (10). The p160 coregulator Steroid Receptor Coactivator (SRC-1) is strongly expressed in br...

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

“…Our analysis of the coexpression of coregulators and steroid receptors identified known relationships, such as the high coexpression between Ncoa1 and Mr in the hippocampus (20). More importantly, this brain-wide analysis provides an overview of potentially unknown relationships between steroid receptors and coregulators.…”

“…Of the three datasets covering expression of Gr, only one was of sufficient quality. Also, Ncoa1, which codes for an important coregulator for ESR1 and GR (1,20), is expressed at low levels and not significantly associated with the two receptors. Consequently, there is the risk for increased false-negative results associated with a genome-wide approach using these data.…”

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

“…A 500 bp SalI-HindIII fragment of exon 2 of the mouse gene was used for glucocorticoid receptor (GR; Veenema et al 2003). The cRNA from corticotropin-releasing hormone (CRH) was transcribed from a 1 kb cDNA insert in pGEM 4 containing the full-length coding region of rat CRH (Lachize et al 2009). …”

Mechanisms of Glucocorticoid Receptor (GR) Mediated Corticotropin Releasing Hormone Gene Expression

“…The best studied of these is SRC-1. The SRC-1a isoform mRNA has been mapped to the PVH, and CRH mRNA levels have been evaluated in SRC-1 knockout mice (Lachize et al 2009). Paradoxically, SRC-1 is associated with crh repression(van der Laan et al 2008).…”