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  • glucocorticoid receptor  (4)
  • 1
    Keywords: RECEPTOR ; MODEL ; GENE ; MICE ; ACTIVATION ; RAT ; RATS ; WATER ; MEMORY ; hippocampus ; LONG-TERM POTENTIATION ; synaptic plasticity ; WATER MAZE ; hormone ; DISRUPTION ; MODULATION ; WILD-TYPE ; glucocorticoid receptor ; RECEPTORS ; RAT-BRAIN ; MEMORY IMPAIRMENT ; ABSENCE ; TARGETED DISRUPTION ; development ; mineralocorticoid receptor ; MUTANTS ; HORMONES ; GLUCOCORTICOIDS ; RECEPTOR GENE ; REACTIVITY ; STRATEGY ; glucocorticoid ; GLUCOCORTICOID RECEPTORS ; Behavioral Reactivity ; Impairment of Hippocampal Function ; II CORTICOSTEROID RECEPTORS ; DAY-OLD CHICKS ; ELECTROCONVULSIVE SHOCK ; SELECTIVE IMPAIRMENT ; HIPPOCAMPAL-LESIONS
    Abstract: 0140,english,Previous studies in rats using the Morris water maze suggested that the processing of spatial information is modulated by corticosteroid hormones through mineralocorticoid and glucocorticoid receptors in the hippocampus. Mineralocorticoid receptors appear to be involved in the modulation of explorative behaviour, while additional activation of glucocorticoid receptors facilitates the storage of information. In the present study we used the water maze task to examine spatial learning and memory in mice homozygous and heterozygous for a targeted disruption of the glucocorticoid receptor gene. Compared with wild-type controls, homozygous and heterozygous mice were impaired in the processing of spatial but not visual information. Homozygous mutants performed variably during training, without specific platform-directed search strategies. The spatial learning disability was partly compensated for by increased motor activity. The deficits were indicative of a dysfunction of glucocorticoid receptors as well as of mineralocorticoid receptors. Although the heterozygous mice performed similarly to wild-type mice with respect to latency to find the platform, their strategy was more similar to that of the homozygous mice. Glucocorticoid receptor-related long-term spatial memory was impaired. The increased behavioural reactivity of the heterozygous mice in the open field points to a more prominent mineralocorticoid receptor- mediated function. The findings indicate that (i) the glucocorticoid receptor is of critical importance for the control of spatial behavioural functions, and (ii) mineralocorticoid receptor-mediated effects on this behaviour require interaction with functional glucocorticoid receptors. Until the development of site-specific, inducible glucocorticoid receptor mutants, glucocorticoid receptor-knockout mice present the only animal model for the study of corticosteroid-mediated effects in the complete absence of a functional receptor
    Type of Publication: Journal article published
    PubMed ID: 9464923
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  • 2
    Keywords: RECEPTOR ; EXPRESSION ; BLOOD ; CELL ; Germany ; IN-VIVO ; liver ; ENZYMES ; GENE ; GENES ; transcription ; METABOLISM ; MICE ; ACTIVATION ; kidney ; TRANSCRIPTION FACTOR ; INDUCTION ; hepatocytes ; MUTANT ; hormone ; DISRUPTION ; TANDEM MASS-SPECTROMETRY ; inactivation ; Jun ; GLUCOSE ; glucocorticoid receptor ; GLUCOCORTICOID-RECEPTOR ; ANTAGONIST ; insulin ; ABSENCE ; ADULT ; ENDOCRINE ; LEADS ; development ; CARBOXYKINASE GTP GENE ; HEPATIC GLUCONEOGENESIS ; PHOSPHOENOLPYRUVATE CARBOXYKINASE ; TYROSINE AMINOTRANSFERASE GENE
    Abstract: Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs) acting on various cell types. GC effects are mediated by the GC receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first 2 d after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia
    Type of Publication: Journal article published
    PubMed ID: 15031319
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; Germany ; IN-VIVO ; INHIBITION ; PATHWAY ; PATHWAYS ; VITRO ; DEATH ; GENE ; MICE ; TRANSDUCTION ; COMPLEX ; COMPLEXES ; MECHANISM ; T-CELL ; T-CELLS ; BINDING ; signal transduction ; CD95 ligand ; CELL-DEATH ; PROMOTER ; MUTATION ; SIGNAL-TRANSDUCTION ; inactivation ; FACTOR-KAPPA-B ; glucocorticoid receptor ; GLUCOCORTICOID-RECEPTOR ; REPRESSION ; CROSS-TALK ; CD95 ; signaling ; molecular ; PROGRAM ; RE ; PH ; regulation ; RHEUMATOID-ARTHRITIS ; INFLAMMATORY RESPONSES ; cell death ; ABILITY ; APOPTOTIC CELLS ; FAS LIGAND ; NEGATIVE REGULATION ; THYMOCYTE DEVELOPMENT
    Abstract: Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs
    Type of Publication: Journal article published
    PubMed ID: 15802531
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  • 4
    Keywords: brain ; RECEPTOR ; EXPRESSION ; Germany ; MODEL ; MODELS ; SYSTEM ; EXPOSURE ; GENE ; PROTEIN ; MICE ; PATIENT ; MECHANISM ; MESSENGER-RNA ; RECEPTOR EXPRESSION ; chromosome ; MOUSE ; TRANSGENIC MICE ; hormone ; YEAST ; STRESS ; PATHOGENESIS ; DNA-BINDING ; Jun ; glucocorticoid receptor ; sensitivity ; BEHAVIOR ; OVEREXPRESSION ; GLUCOCORTICOID-RECEPTOR ; signaling ; molecular ; regulation ; KNOCKOUT MICE ; NEUROTROPHIC FACTOR ; FOREBRAIN ; RAT HIPPOCAMPUS ; depression ; DEXAMETHASONE-CRH TEST ; helplessness
    Abstract: Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR(+/-)) with a 50% GRgene dose reduction, and (2) mice overexpressingGR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR(+/-) mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR(+/-) mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression
    Type of Publication: Journal article published
    PubMed ID: 15987954
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