Mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and a host of other mental retardation syndromes in both males and females. RTT results from loss-of-function mutations of MECP2, which binds to target DNA and recruits Sin3A and histone deacetylases to silence transcription. MeCP2 is part of a larger family of genes, the methyl-CpG-binding domain (MBD) family, which is conserved from fly through humans. Overexpression of MECP2 in Drosophila using the UAS-GAL4 system produces a phenotype, possibly by competing with MBD genes. I propose to continue characterization of the full-length lines and create additional transgenic flies: two lines which overexpress MECP2 mutations commonly found in Rett patients and one line which produces MeCP2 without the MBD region. Secondly, I will characterize the Drosophila MBD gene CG10042 for native RNA and protein expression patterns. Then I will investigate its function through P-element mutagenesis and RNAi with genomic eDNA hybrids. I will characterize all resulting phenotypes and use these strains to identify modifiers of MeCP2 and/or CG10042 through an F 1 modifier screen to gain insight into pathways of MeCP2 function, which until now has been studied only in vitro. Through the proposed genetic studies, I hope to identify proteins that can be then studied to investigate the mechanisms of the mental and neurological dysfunction in Rett and related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM067501-02
Application #
6800378
Study Section
Special Emphasis Panel (ZRG1-F08 (20))
Program Officer
Toliver, Adolphus
Project Start
2003-09-01
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$30,924
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Cukier, Holly N; Perez, Alma M; Collins, Ann L et al. (2008) Genetic modifiers of MeCP2 function in Drosophila. PLoS Genet 4:e1000179