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Human Molecular Genetics Advance Access published online on July 7, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi229
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received April 25, 2005
Revised June 15, 2005
Accepted June 23, 2005

Article

Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome

Ulrike A. Nuber 1, Skirmantas Kriaucionis 2, Tim C. Roloff 1, Jacky Guy 2, Jim Selfridge 2, Christine Steinhoff 1, Ralph Schulz 1, Bettina Lipkowitz 1, H. Hilger Ropers 1, Megan C. Holmes 3, and Adrian Bird 2*

1 Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany
2 The Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, UK
3 Department of Clinical Neurosciences, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK

* To whom correspondence should be addressed.
Adrian Bird, E-mail: a.bird{at}ed.ac.uk


  Abstract

Rett syndrome (RTT) is a severe form of mental retardation in girls, which is caused by spontaneous mutations in the X-linked gene MECP2. How the loss of MeCP2 function leads to RTT is currently unknown. Mice lacking the Mecp2 gene initially show normal postnatal development but later acquire neurological phenotypes, including heightened anxiety, that resemble RTT. The MECP2 gene encodes a methyl-CpG-binding protein that can act as a transcriptional repressor. Using cDNA microarrays, we found that Mecp2-null animals differentially express several genes that are induced during stress response by glucocorticoids. Increased levels of mRNAs for plasma glucocorticoid-inducible kinase 1 (Sgk) and FK506-binding protein 51 (Fkbp5) were observed before and after onset of neurological symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 is bound to the Fkbp5 and Sgk genes in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, our data raise the possibility that disruption of MeCP2-dependent regulation of stress-responsive genes contributes to the symptoms of RTT.


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