Analysis of glucocorticoid and mineralocorticoid signalling by gene targeting.

To get a better understanding of the role of glucocorticoid and mineralocorticoid signalling during development and in whole animal physiology, we have disrupted the mouse glucocorticoid and mineralocorticoid receptor gene by gene targeting. Most of the mice with a disrupted glucocorticoid receptor gene die within the first hours after birth due to severe lung atelectasis. Perinatal induction of gluconeogenic enzymes in the liver is impaired. Feed back control of the glucocorticoid synthesis via the hypothalamic-pituitary-adrenal axis is perturbed leading to increased plasma levels of corticosterone and adrenocorticotrophic hormone. Increased activity of the hypothalamic-pituitary-adrenal axis results in extensive hypertrophy and hyperplasia of the cortical zones of the adrenal and induction of genes involved in steroid biosynthesis. The adrenal medulla is disorganized and severely reduced in size; cells capable of adrenaline synthesis are missing. Mineralocorticoid receptor deficient mice die around day 10 after birth. Weight loss precedes death of homozygous mutant mice and is correlated with an increase in the haematocrit. As a consequence of this mutation plasma levels of renin, angiotensin II, and aldosterone are highly elevated.