Human Molecular Genetics Advance Access originally published online on July 7, 2005
Human Molecular Genetics 2005 14(15):2247-2256; doi:10.1093/hmg/ddi229
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Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome
1Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany, 2The Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, UK and 3Department of Clinical Neurosciences, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
* To whom correspondence should be addressed. Tel: +44 1316505670; Fax: +44 1316505379; Email: a.bird{at}ed.ac.uk
Received April 25, 2005; Revised June 15, 2005; Accepted June 23, 2005
Rett syndrome (RTT) is a severe form of mental retardation, 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 the stress response by glucocorticoids. Increased levels of mRNAs for serum 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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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