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Articles by G Schutz
Total Records ( 3 ) for G Schutz
  M. V Schmidt , V Sterlemann , K Wagner , B Niederleitner , K Ganea , C Liebl , J. M Deussing , S Berger , G Schutz , F Holsboer and M. B. Muller
 

A tight regulation of hypothalamic-pituitary-adrenal (HPA) axis activity is essential for successful adaptation to stressful stimuli. Disruption of normal HPA axis development is a main risk factor for diseases such as posttraumatic stress disorder or depression, but the molecular mechanisms that lead to these long-term consequences are poorly understood. Here, we test the hypothesis that the pituitary glucocorticoid receptor (GR) is involved in regulating HPA axis function in neonatal and adult animals. Furthermore, we investigate whether postnatal hypercortisolism induced by pituitary GR deficiency is a main factor contributing to the persistent effects of early-life stress. Conditional knockout mice with a deletion of the GR at the pituitary (GRPOMCCre) show excessive basal corticosterone levels during postnatal development, but not in adulthood. The hypercortisolemic state of neonatal GRPOMCCre mice is accompanied by central gene expression changes of CRH and vasopressin in the paraventricular nucleus, but these alterations normalize at later ages. In adult mice, pituitary GR deficiency results in impaired glucocorticoid negative feedback. Furthermore, adult GRPOMCCre mice display a more active coping strategy in the forced swim test, with no alterations in anxiety like behavior or cognitive functions. Postnatal GR antagonist treatment is able to prevent the long-term behavioral effects in GRPOMCCre mice. In conclusion, we show that pituitary GRs are centrally involved in regulating HPA axis activity in neonates and mediate negative feedback regulation in adult animals. Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition.

  F Oury , V. K Yadav , Y Wang , B Zhou , X. S Liu , X. E Guo , L. H Tecott , G Schutz , A. R Means and G. Karsenty
 

Serotonin is a bioamine regulating bone mass accrual differently depending on its site of synthesis. It decreases accrual when synthesized in the gut, and increases it when synthesized in the brain. The signal transduction events elicited by gut-derived serotonin once it binds to the Htr1b receptor present on osteoblasts have been identified and culminate in cAMP response element-binding protein (CREB) regulation of osteoblast proliferation. In contrast, we do not know how brain-derived serotonin favors bone mass accrual following its binding to the Htr2c receptor on neurons of the hypothalamic ventromedial nucleus (VMH). We show here—through gene expression analysis, serotonin treatment of wild-type and Htr2c–/– hypothalamic explants, and cell-specific gene deletion in the mouse—that, following its binding to the Htr2c receptor on VMH neurons, serotonin uses a calmodulin kinase (CaMK)-dependent signaling cascade involving CaMKKβ and CaMKIV to decrease the sympathetic tone and increase bone mass accrual. We further show that the transcriptional mediator of these events is CREB, whose phosphorylation on Ser 133 is increased by CaMKIV following serotonin treatment of hypothalamic explants. A microarray experiment identified two genes necessary for optimum sympathetic activity whose expression is regulated by CREB. These results provide a molecular understanding of how serotonin signals in hypothalamic neurons to regulate bone mass accrual and identify CREB as a critical determinant of this function, although through different mechanisms depending on the cell type, neuron, or osteoblast in which it is expressed.

  D. L Ahlbory Dieker , B. D Stride , G Leder , J Schkoldow , S Trolenberg , H Seidel , C Otto , A Sommer , M. G Parker , G Schutz and T. M. Wintermantel
 

The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor (ER), which regulates transcription by several mechanisms. Because the tissue-specific effects of some ER ligands may be caused by tissue-specific transcriptional mechanisms of ER, we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver. We used a genetic mouse model that dissects DNA binding-dependent vs. independent transcriptional regulation elicited by ER. The EAAE mutant harbors amino acid exchanges at four positions of the DNA-binding domain (DBD) of ER. This construct was knocked in the ER gene locus to produce ER(EAAE/EAAE) mice devoid of a functional ER DBD. The phenotype of the ER(EAAE/EAAE) mice resembles the general loss-of-function phenotype of ER knockout mutant mice with hypoplastic uteri, hemorrhagic ovaries, and impaired mammary gland development. In agreement with this phenotype, the expression pattern of the ER(EAAE/EAAE) mutant mice in liver obtained by genome-wide gene expression profiling supports the observation of a near-complete loss of estrogen-dependent gene regulation in comparison with the wild type. Further gene expression analyses to validate the results of the microarray data were performed by quantitative RT-PCR. The analyses indicate that both gene activation and repression by estrogen-bound ER rely on an intact DBD in vivo.

 
 
 
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