Understanding the Pathogenic Mechanisms of Rett Syndrome

点击翻译按钮获取中文摘要

Mutations in methyl-CpG binding protein 2 (MECP2) gene cause Rett Syndrome (RTT), a neurodevelopmental disorder that afflicts about 1 in 10,000 girls. To understand the pathogenesis of RTT, we previously developed and characterized mouse models recapitulating RTT-associated missense mutations, MeCP2 T158M and R106W, and examined MeCP2-dependent gene expression programs in neuronal cell types of interest. We found that 1) both mutations impair MeCP2 binding to chromatin, resulting in RTT-like phenotypes in mice, but, elevation of MeCP2 mutant protein expression increase the binding of MeCP2 to chromatin and ameliorate RTT-like phenotypes in vivo, raising a new direction to develop therapeutics for RTT; 2) MeCP2 plays a necessary and sufficient role in forebrain GABAergic interneurons mediating neuronal event-related potentials (ERPs), supporting a key role for MeCP2 to regulate information processing; and 3) By developing a Cre-dependent biotin tagging system, we uncovered that MeCP2 modulates gene transcription in a mutation-dependent, cell type-specific, and in both cell and non-cell autonomous manner, particularly in mosaic females. These findings have set the premise to uncover the molecular mechanisms by which MeCP2 modulates cell type-specific gene expression, investigate the molecular etiology of RTT in heterozygous females, and test the causality of MeCP2-dependent molecular pathways that underlie the pathogenesis of RTT. With the combined genetic, genomic, molecular and cellular approaches, we hope to not only reveal novel insight into the pathogenic mechanisms of RTT, but also to expedite the development of mechanism-based therapeutics to improve treatment for RTT. Moreover, our proposed study will provide the research community at large with innovative tools and resources to investigate the epigenetic mechanisms underlying a variety of biological processes and diseases.