Evaluation of steroid receptor function by gene targeting in mice.
Corticosteroid hormones regulate a variety of developmental, physiological and pathological processes via their cognate receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Using modern genetic technologies, including bacterial artificial chromosome-based transgenesis and conditional gene targeting, we have generated a panel of tissue-specific and function-selective mutations of the two corticosteroid hormone receptors in the mouse. These mouse models have allowed us to gain new insights into corticosteroid hormone signaling in vivo. By investigating a hepatocyte-specific GR mutation, it has been possible to define a novel biological action of GR, namely to function as a coactivator for Stat5-mediated gene transcription in the control of body growth. The investigation of brain-specific mutations have not only allowed us to better understand hypothalamo-pituitary-adrenal (HPA) axis regulation by glucocorticoids, but also to analyse corticosteroid action in various aspects of brain function like anxiety-related or addiction-related behaviour, and learning and memory. A function-selective mutation in the GR has allowed us to dissect different pathways in the gene expression regulation by this receptor, namely to separate DNA response element-binding dependent gene activation from response element-independent gene regulation via interference with other transcription factors. These different transcriptional activities of GR play an important role in glucocorticoid-mediated immunosuppression.
Wintermantel
Tim M
TM
Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Berger
Stefan
S
Greiner
Erich F
EF
Schütz
Günther
G
D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003071:Cognition / Q000502:physiology; D005246:Feedback; D018390:Gene Targeting / Q000379:methods*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007107:Immune System / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists; D016296:Mutagenesis; D010913:Pituitary-Adrenal System / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid