Feedback Control of Glucocorticoid Production is Established during Fetal Development

Holger M. Reichardt, Günther Schütz

Glucocorticoids are involved in the regulation of metabolic, immunological, and developmental processes. Their synthesis is tightly controlled by feedback regulation through the hypothalamus-pituitary-adrenal (HPA) axis, allowing the organism to respond to stress in an adequate manner and to adapt to new situations. Disturbance of these regulatory mechanisms leads to major human diseases. By generating mice with a targeted mutation in the glucocorticoid receptor (GR) locus, it was possible to analyze the mechanism by which glucocorticoids control the HPA axis, under conditions where at least part of the feedback control was absent early in development. RNase-protection and in situ hybridization assays were used to compare messenger RNA (mRNA) levels of genes involved in the control of the HPA axis in both GR-mutant and wild-type animals. Negative feedback regulation of the HPA axis by glucocorticoids, which is established around Day E16.5 of embryonic development in wild-type mice, does not occur in GR-mutants, resulting in an increased expression of proopiomelanocortin mRNA in the anterior lobe of the pituitary and of corticotropin-releasing hormone mRNA in the paraventricular nucleus of the hypothalamus. However, the expression of both arginine vasopressin and mineralocorticoid receptor in the brain is not affected. In the neurointermediate lobe of the pituitary, expression of the proopiomelanocortin gene was inversely regulated, compared with its expression in the anterior lobe. GR-dependent regulation of the HPA axis is established during fetal development, suggesting that maternal factors have an important role in influencing the HPA axis of the adult offspring.