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

Timothy J. Cole, Julie A. Blendy, A. Paula Monaghan, Kerstin Krieglstein, Wolfgang Schmid, Adriano Aguzzi, Giamila Fantuzzi, Edith Hummler, Klaus Unsicker, Günther Schütz

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752 Citations (Scopus)

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 11β-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.

Original languageEnglish
Pages (from-to)1608-1621
Number of pages14
JournalGenes & Development
Volume9
Issue number13
DOIs
Publication statusPublished - 1 Jul 1995
Externally publishedYes

Keywords

  • chromaffin cells
  • gene targeting
  • Glucocorticoids
  • lung development
  • steroid hormone receptor

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