Genetic Dissection of Glucocorticoid (GR) and Mineralocorticoid Receptor (MR) Function in Mice

G. Schütz

Department of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.

Glucocorticoids and mineralocorticoids are involved in numerous physiological processes important to maintain metabolic, cardiovascular, central nervous and immune system homeostasis. Germ line and somatic gene targeting allows the characterization of the various functions and molecular modes of action of these receptors. Most of the effects of the glucocorticoid receptor are mediated via activation and repression of gene expression. To separate activities of the GR, a point mutation was introduced which allowed to characterize and distinguish functions dependent on GR-binding to DNA from those mediated by protein/protein interaction leading to gene repression as well as gene activation. Cell/tissue-specific mutations of the gluco- and mineralocorticoid receptor is the basis for the evaluation of their cell-specific functions and characterization of target genes by expression profiling. The GR gene was inactivated in parenchymal cells of the liver, in thymocytes, monocytes/macrophages, skin and brain, respectively. The absence of GR in hepatocytes leads to a dramatic reduction of body size. We could show that growth hormone (GH) signalling mediated by STAT5 in hepatocytes is impaired in these mice leading to lower synthesis of IGF-I and other STAT-dependent mRNAs. Interestingly, dimerization-defective GR mice show wild-type levels of these mRNAs and have a normal body size. These findings strongly suggest a model in which GR functions as a co-activator for STAT5 transcription upon GH stimulation and reveal an essential role of GC signalling through hepatic GR in the control of body growth. The MR is expressed in many regions of the brain with particular high levels in neurons of the hippocampus. Inactivation of MR in the forebrain leads to impaired learning and memory. A comparison of GR and MR functions in the brain will also be discussed.