Understanding the Pathogenic Mechanisms of Rett Syndrome

甲基CpG结合蛋白2（MECP 2）基因突变导致Rett综合征（RTT）， 每10,000个女孩中就有一个患有神经发育障碍。为了了解RTT的发病机制， 我们以前开发和表征了小鼠模型，重现了RTT相关的错义， 突变，MeCP 2 T158 M和R106 W，并检查了MeCP 2依赖的基因表达程序， 感兴趣的神经元细胞类型。我们发现1）两种突变都损害MeCP 2与染色质的结合， 导致小鼠中的RTT样表型，但是，MeCP 2突变蛋白表达的升高增加了小鼠中的RTT样表型。 MeCP 2与染色质的结合并改善体内RTT样表型，提出了新的方向， 开发RTT的治疗方法; 2）MeCP 2在前脑GABA能中发挥必要且充分的作用 介导神经元事件相关电位（ERP）的中间神经元，支持MeCP 2在 调节信息加工; 3）通过开发依赖于Cre的生物素标记系统， 发现MeCP 2以突变依赖性、细胞类型特异性和细胞增殖性的方式调节基因转录。 细胞和非细胞自主的方式，特别是在马赛克女性。这些发现使 揭示MeCP 2调节细胞类型特异性基因的分子机制的前提 表达，研究杂合子女性RTT的分子病因学，并测试 MeCP 2依赖性分子途径是RTT发病机制的基础。与组合 基因、基因组、分子和细胞的方法，我们希望不仅能揭示新的见解， RTT的致病机制，而且还可以加快基于机制的治疗方法的发展 来改善RTT的治疗此外，我们拟议的研究将为研究界提供 大与创新的工具和资源，以调查表观遗传机制的基础上的各种 生物过程和疾病。

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.