Genetic dissection of gluco- and mineralocorticoid receptor function in mice

Abstract

Nuclear hormone receptors function to transduce hormonal signals into transcriptional responses by controlling the activity of specific target genes. These target genes comprise a genetic network whose coordinate activity defines the physiological responses to hormonal signals. Dissecting nuclear hormone receptor functions in vivo by gene inactivation and transgenic strategies represents an invaluable and powerful approach to increase our knowledge of these genetic networks and their physiological functions. Glucocorticoids and mineralocorticoids are involved in numerous physiological processes important to maintain metabolic, cardiovascular, central nervous, and immune system homeostasis. Germline and somatic gene targeting as well as an increased dosage of the glucocorticoid receptor (GR) allows the characterization of the various functions and molecular modes of action of this receptor. Most of the effects of the GR are mediated via activation and repression of gene expression. To separate activating from repressing functions of the GR, a point mutation was introduced which allowed us to characterize and distinguish functions dependent on GR binding to DNA from those mediated by protein/protein interaction. Cell/tissue-specific mutations of the gluco- and mineralocorticoid receptor is the basis for the evaluation of their cell-specific functions, including the characterization of target genes of the receptors in order to describe their specific effects on different targets.