Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 48, Pages 18267-18272Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0608702103
Keywords
autism; corticotropin-releasing hormone; methyl-CpG-binding protein 2
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Funding
- NCRR NIH HHS [P41 RR0250, P41 RR002250] Funding Source: Medline
- NICHD NIH HHS [P30 HD024064, R01HD40301, P01 HD040301] Funding Source: Medline
- NIMH NIH HHS [F30 MH068996] Funding Source: Medline
- NLM NIH HHS [T15 LM007093, 5T15LM07093] Funding Source: Medline
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Rett syndrome (RTT), a postnatal neurodevelopmental disorder, is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Children with RTT display cognitive and motor abnormalities as well as autistic features. We studied mice bearing a truncated Mecp2 allele (Mecp2(308/Y) mice) and found evidence of increased anxiety-like behavior and an abnormal stress response as evidenced by elevated serum corticosterone levels. We found increased corticotropin-releasing hormone (Crh) gene expression in the paraventricular nucleus of the hypothalamus, the central amygdala, and the bed nucleus of the stria terminalis. Finally, we discovered that MeCP2 binds the Crh promoter, which is enriched for methylated CpG dinucleotides. In contrast, the MeCP2308 protein was not detected at the Crh promoter. This study identifies Crh as a target of MeCP2 and implicates Crh overexpression in the development of specific features of the Mecp2(308/Y) mouse, thereby providing opportunities for clinical investigation and therapeutic intervention in RTT.
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