Mutagenesis of the glucocorticoid receptor in mice

The glucocorticoid receptor is an ubiquitously expressed transcription fact or involved in the regulation of many different physiological processes. Ac tivated by glucocorticoids the receptor regulates transcription positively or negatively either by direct binding to DNA or by protein-protein interac tions. In order to define the role of the receptor during development and i n physiology several mutations have been generated in the mouse. Mice with a disrupted glucocorticoid receptor gene die shortly after birth due to res piratory failure indicating an important role of the receptor in lung funct ion. Transcription of genes encoding gluconeogenic enzymes in the liver is decreased, proliferation of erythroid progenitors is impaired and the HPA a xis is strongly upregulated. To analyze molecular mechansims of glucocortic oid receptor action in vivo a point mutation has been introduced into the m ouse genome which allows to separate DNA-binding-dependent from DNA-binding -independent actions of the receptor. Mice homozygous for the point mutatio n survive indicating that DNA-binding of the receptor is not required for s urvival. Induction of glucoconegenic enzymes and proliferation of erythroid progenitors however is impaired. Interestingly, repression of corticotropi n releasing factor (CRF) synthesis is maintained, whereas proopiomelanocort in (POMC) expression is upregulated. Since mice with a disrupted glucocorti coid receptor gene die shortly after birth attempts using the Cre/loxP-reco mbination system are made to bypass early lethality and to study the functi on of the receptor in defined cell types of adult animals. (C) 1999 Elsevie r Science Ltd. All rights reserved.