title: Genetic modifiers of MeCP2 function in Drosophila.
abstract: The levels of methyl-CpG-binding protein 2 (MeCP2) are critical for normal post-natal development and function of the nervous system. Loss of function of MeCP2, a transcriptional regulator involved in chromatin remodeling, causes classic Rett syndrome (RTT) as well as other related conditions characterized by autism, learning disabilities, or mental retardation. Increased dosage of MeCP2 also leads to clinically similar neurological disorders and mental retardation. To identify molecular mechanisms capable of compensating for altered MeCP2 levels, we generated transgenic Drosophila overexpressing human MeCP2. We find that MeCP2 associates with chromatin and is phosphorylated at serine 423 in Drosophila, as is found in mammals. MeCP2 overexpression leads to anatomical (i.e., disorganized eyes, ectopic wing veins) and behavioral (i.e., motor dysfunction) abnormalities. We used a candidate gene approach to identify genes that are able to compensate for abnormal phenotypes caused by MeCP2 increased activity. These genetic modifiers include other chromatin remodeling genes (Additional sex combs, corto, osa, Sex combs on midleg, and trithorax), the kinase tricornered, the UBE3A target pebble, and Drosophila homologues of the MeCP2 physical interactors Sin3a, REST, and N-CoR. These findings demonstrate that anatomical and behavioral phenotypes caused by MeCP2 activity can be ameliorated by altering other factors that might be more amenable to manipulation than MeCP2 itself.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Holly N
authors.initials: HN
authors.lastname: Cukier
authors.forename: Alma M
authors.initials: AM
authors.lastname: Perez
authors.forename: Ann L
authors.initials: AL
authors.lastname: Collins
authors.forename: Zhaolan
authors.initials: Z
authors.lastname: Zhou
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002843:Chromatin / Q000378:metabolism; D004330:Drosophila / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D010641:Phenotype; D010766:Phosphorylation; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012694:Serine
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