Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation.

TLDR

The study investigates the role of the glucocorticoid receptor in glucocorticoid physiology and development by generating GR‑deficient mice. GR‑deficient mice were produced by gene targeting. GR‑/‑ mice die within hours of birth from respiratory failure, exhibit severely atelectatic lungs with delayed development, reduced hepatic gluconeogenic capacity, hyperactive HPA axis, enlarged adrenal cortices, absence of medullary tissue and adrenaline, and lack adrenergic chromaffin cells while retaining scattered noradrenergic cells, indicating that glucocorticoid signaling is essential for adrenergic chromaffin cell proliferation and survival.

Abstract

The role of the glucocorticoid receptor (GR) in glucocorticoid physiology and during development was investigated by generation of GR-deficient mice by gene targeting. GR -/- mice die within a few hours after birth because of respiratory failure. The lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11 beta-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These results suggest that the adrenal medulla may be formed from two different cell populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic population that differentiates normally in the absence of glucocorticoid signaling.