Molecular genetic analysis of glucocorticoid signaling using the Cre/loxP system

Glucocorticoids (GC) are involved in a plethora of physiological processes that range from the regulation of the stress response and the control of th e immune system to modulation of behavior. Most GC effects are mediated by the glucocorticoid receptor (GR) via activation and repression of gene expr ession. Whereas in most cases activation requires DNA binding of the recept or, repression is usually mediated by protein-protein interaction with othe r transcription factors. To decipher the molecular mode of action of GR, mi ce were generated by gene targeting carrying a point mutation in one of the dimerization domains, thus abrogating DNA binding by GR. Analysis of these mice demonstrated that thymocyte apoptosis and stress erythropoiesis requi re the DNA binding-dependent function of GR, whereas lung development and t he anti-inflammatory activity of GR are mediated by protein-protein interac tion. Furthermore, to study the role of GC in the brain, mice were generate d specifically lacking GR function in the nervous system. Using these mice we demonstrated that GR is essential for the regulation of the HPA-axis and the stress response, as well as for the control of emotional behavior, Tak en together, gene targeting using the Cre/IoxP system proved to be highly v aluable for the analysis of both molecular mechanism and tissue-specific fu nctions of the GR.