Genetic modifiers of MeCP2 function in Drosophila

Holly N. Cukier, Alma M. Perez, Ann L. Collins, Zhaolan Zhou, Huda Y. Zoghbi, Juan Botas

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Article numbere1000179
JournalPLoS genetics
Volume4
Issue number9
DOIs
StatePublished - Sep 2008

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Cukier, H. N., Perez, A. M., Collins, A. L., Zhou, Z., Zoghbi, H. Y., & Botas, J. (2008). Genetic modifiers of MeCP2 function in Drosophila. PLoS genetics, 4(9), [e1000179]. https://doi.org/10.1371/journal.pgen.1000179