TARGETED DISRUPTION OF THE GLUCOCORTICOID RECEPTOR GENE BLOCKS ADRENERGIC CHROMAFFIN CELL-DEVELOPMENT AND SEVERELY RETARDS LUNG MATURATION

The role of the glucocorticoid receptor (GR) in glucocorticoid physiol ogy and during development was investigated by generation of GR-defici ent mice by gene targeting. GR -/- mice die within a few hours after b irth because of respiratory failure. The lungs at birth are severely a telectatic, and development is impaired from day 15.5 p.c. Newborn liv ers have a reduced capacity to activate genes for key gluconeogenic en zymes. feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocor ticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Ac cordingly, adrenal glands are enlarged because of hypertrophy of the c ortex, resulting in increased expression of key cortical steroid biosy nthetic enzymes, such as side-chain cleavage enzyme, steroid 11 beta-h ydroxylase, and aldosterone synthase. Adrenal glands lack a central me dulla and synthesize no adrenaline. They contain no adrenergic chromaf fin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These result s suggest that the adrenal medulla may be formed from two different ce ll populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic popula tion that differentiates normally in the absence of glucocorticoid sig naling.