MOLECULAR-GENETIC ANALYSIS OF GLUCOCORTICOID AND MINERALOCORTICOID SIGNALING IN DEVELOPMENT AND PHYSIOLOGICAL PROCESSES

To understand the role of glucocorticoid and mineralocorticoid signall ing during development and in whole animal physiology, we have disrupt ed the mouse glucocorticoid and mineralocorticoid receptor gene by gen e targeting. Most of the mice with a disrupted glucocorticoid receptor gene die within the first hours after birth due to severe lung atelec tasis. Perinatal induction of gluconeogenic enzymes in the liver is im paired Regulation of the glucocorticoid synthesis via the hypothalamic -pituitary-adrenal axis is perturbed, leading to increased plasma leve ls of corticosterone and adrenocorticotrophic hormone. Activation of t he hypothalamic-pituitary-adrenal axis results in extensive hypertroph y and hyperplasia of the cortical zones of the adrenal and induction o f genes involved in steroid biosynthesis. The adrenal medulla is disor ganized and severely reduced in size; no cells capable of adrenaline s ynthesis can be detected. Mineralocorticoid receptor deficient mice di e mainly at day 9/10 after birth. Weightless precedes death of homozyg ous mutant mice and is correlated with an increase in the haematocrit. As a consequence of this mutation, plasma levels of renin and aldoste rone are highly elevated.