Corticotropin-releasing hormone expression is the major target for glucocorticoid feedback-control at the hypothalamic level.

Glucocorticoid production is controlled via the hypothalamo-pituitary-adrenal (HPA) axis by a negative feedback mechanism involving the glucocorticoid receptor (GR). A major site of regulation is the hypothalamus, where the GR is thought to repress the expression of genes such as corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). To define the role of the GR in this feedback loop in more detail, the content of CRH, AVP and neurophysin in the median eminence of mice carrying a targeted disruption of the GR gene was studied using immunohistochemistry. GR-deficient mice were found to contain five times more CRH in the median eminence than wild-type littermates. In contrast, no significant change in the content of AVP was observed in the outer layer of the median eminence and neurophysin was also only moderately increased. Our studies suggest that, at the hypothalamic level, CRH synthesis is the major target for feedback control by the GR and that transcriptional control of AVP and neurophysin plays only a supportive role in this process.

Glucocorticoid signalling--multiple variations of a common theme.

Recent advances in molecular genetics have brought us closer to answering the question as to which mechanisms are used by steroid hormone receptors to control transcription. While binding to specific response elements in the promoter and enhancer regions of many genes has for a long time been considered as the major mode of action, a growing number of alternative transcriptional control mechanisms have been identified in the last couple of years. With the recent finding that DNA binding of the glucocorticoid receptor is not essential for survival, mechanisms depending on cross-talk with other transcription factors through protein-protein interactions have gained attention. In this mini-review, we will discuss the roles of DNA binding-dependent and -independent transcriptional modes of action in development and physiology as exemplified by the analysis of glucocorticoid receptor function.