Human Molecular Genetics Advance Access published online on April 15, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp181
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Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus
1 Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA 2 Biochemistry, Baylor College of Medicine, Houston, TX 77030 USA 3 Neuroscience, Baylor College of Medicine, Houston, TX 77030 USA 4 Pediatrics and Neurology, Baylor College of Medicine, Houston, TX 77030 USA 5 Programs in Cell and Molecular Biology and Developmental Biology, Baylor College of Medicine, Houston, TX 77030 USA 6 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030 USA 7 Current affiliation: Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
* Corresponding author: Huda Y. Zoghbi, M.D., Baylor College of Medicine, One Baylor Plaza, T807, Houston, TX 77030, Tel: 713-798-6558, Fax: 713-798-8728, Email: hzoghbi{at}bcm.edu
Received February 5, 2009; Revised April 8, 2009; Accepted April 8, 2009
A group of postnatal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
# These authors contributed equally to this work and should be considered co-first authors