Genetic Modifiers of MeCP2 Function in Drosophila

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

doi:10.1371/journal.pgen.1000179

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.

Highlights

Research in the last decade has linked the methyl-CpG-binding protein 2 (MeCP2) with a variety of related neurological disorders [1]
Loss of MeCP2 function can lead to clinically distinct conditions characterized by autism, learning disability, and mental retardation
Increased levels of MeCP2 leads to related neurological disorders and mental retardation as well

Summary

Introduction

Research in the last decade has linked the methyl-CpG-binding protein 2 (MeCP2) with a variety of related neurological disorders [1]. Examples of evolutionarily conserved chromatin remodeling proteins include members of the Polycomb and trithorax groups (Pc-G and trx-G, respectively), as well as proteins involved in histone tail modification [17,18] Many of these proteins act in protein complexes that function antagonistically to promote either activation or repression of target genes [17,19,20,21]. We hypothesized that genetic screening in transgenic flies expressing human MeCP2 may permit the identification of genes capable of compensating the phenotypes caused by altered MeCP2 levels These genetic modifiers may include genes that function antagonistically to MeCP2 in chromatin remodeling, and perhaps other genes modulating MeCP2 functions or interactions.

Methods

Discussion

Conclusion