FEEDBACK-CONTROL OF GLUCOCORTICOID PRODUCTION IS ESTABLISHED DURING FETAL DEVELOPMENT

Background: Glucocorticoids are involved in the regulation of metaboli c, immunological, and developmental processes. Their synthesis is tigh tly controlled by feedback regulation through the hypothalamus-pituita ry-adrenal (HPA) axis, allowing the organism to respond to stress in a n adequate manner and to adapt to new situations. Disturbance of these regulatory mechanisms leads to major human diseases. By generating mi ce with a targeted mutation in the glucocorticoid receptor (GR) locus, it was possible to analyze the mechanism by which glucocorticoids con trol the HPA ards, under conditions where at least part of the feedbac k control was absent early in development. Materials and Methods: RNas e-protection and in situ hybridization assays were used to compare mes senger RNA (mRNA) levels of genes involved in the control of the HPA a xis in both GR-mutant and wild-type animals. Results: Negative feedbac k 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 proopiome lanocortin mRNA in the anterior lobe of the pituitary and of corticotr opin-releasing hormone mRNA in the paraventricular nucleus of the hypo thalamus. However, the expression of both arginine vasopressin and min eralocorticoid receptor in the brain is not affected. In the neurointe rmediate lobe of the pituitary, expression of the proopiomelanocortin gene was inversely regulated, compared with its expression in the ante rior lobe. Conclusions: GR-dependent regulation of the HPA axis is est ablished during fetal development, suggesting that maternal factors ha ve an important role in influencing the HPA axis of the adult offsprin g.