Rett syndrome (RTT), an X-linked neurodevelopmental disorder, is the leading cause of mental retardation and autistic features in females. RTT results from loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), which binds to target DNA and recruits Sin3A and histone deacetylases to silence transcription. Although MeCP2 is ubiquitously expressed, the Rett phenotype is predominantly neurological; I hypothesize that loss of MeCP2 function leads to altered expression of neuronal genes, and that the neural specificity of the phenotype is mediated by interactions of MeCP2 with neuronal-specific factors. The overarching goal of this proposal is to test these hypotheses by evaluating the effects of MeCP2 on neuronal gene expression and to probe for interactions with neuronal genes to uncover potential novel functions. Analysis of a mouse bearing a transgene for human MeCP2 under the endogenous promoter will complement ongoing analysis of a mouse line bearing a loss-of-function mutation. Microarray analysis will help identify downstream targets of MeCP2. Finally, insight into MeCP2 function should be gained by identifying proteins that interact with the C-terminal end of MeCP2, which has recently been shown to contain homology to neural-specific transcription factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH065097-02
Application #
6529004
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Curvey, Mary F
Project Start
2002-09-19
Project End
Budget Start
2002-09-19
Budget End
2003-09-18
Support Year
2
Fiscal Year
2002
Total Cost
$28,361
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Collins, Ann L; Levenson, Jonathan M; Vilaythong, Alexander P et al. (2004) Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet 13:2679-89
Stancheva, Irina; Collins, Anne L; Van den Veyver, Ingatia B et al. (2003) A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos. Mol Cell 12:425-35