Understanding the Pathogenic Mechanisms of Rett Syndrome

标题 Rett综合征的发病机制 摘要 甲基-CpG结合蛋白2（MECP 2）基因突变导致自闭症谱系障碍Rett 综合征（RTT）。为了了解RTT的发病机制，我们以前开发并表征了一种 小鼠模型重现RTT相关的错义突变，MeCP 2 T158 A。我们发现老鼠 具有T158 A突变的小鼠显示与Mecp 2缺失小鼠相似的RTT样表型。T158 A突变 降低MeCP 2与甲基化DNA的结合并降低MeCP 2蛋白稳定性。小鼠 MeCP 2功能障碍还显示神经元事件相关电位（ERP）的年龄依赖性损害。 表明神经回路受损此外，我们正在进行的工作支持MeCP 2在以下方面的作用： 以细胞类型特异性方式调节基因转录和树突发育。我们一起努力， 这些发现导致了一系列关于RTT致病机制的新问题。我们 我建议在以下具体目标中解决这些问题：1）确定甲基-DNA结合的作用， MeCP 2在RTT样表型的病因学中的作用; 2）分析MeCP 2在不同神经元中的作用， 调节信息处理的细胞; 3）研究 MeCP 2调节细胞类型特异性神经元功能。结合遗传基因组行为 和神经生理学的方法，我们希望不仅揭示新的见解致病 RTT的潜在机制，而且还可以加快基于机制的治疗方法的发展， 集中在MeCP 2甲基DNA结合和特定的神经元类型。此外，我们提出的研究 将为整个研究界提供创新的工具和资源，以调查 表观遗传机制是各种生物过程和疾病的基础。

Title Understanding the Pathogenic Mechanisms of Rett Syndrome Abstract Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause the autism spectrum disorder Rett Syndrome (RTT). To understand the pathogenesis of RTT, we previously developed and characterized a mouse model recapitulating an RTT-associated missense mutation, MeCP2 T158A. We found that mice with T158A mutation show similar RTT-like phenotypes to that of Mecp2-null mice. T158A mutation decreases the binding of MeCP2 to methylated DNA and reduces MeCP2 protein stability. Mice with MeCP2 dysfunction also show age-dependent impairment of neuronal event-related potentials (ERPs) indicative of disrupted neural circuitry. Moreover, our ongoing work supports a role of MeCP2 in modulation of gene transcription and dendritic development in a cell-type specific manner. Together, these findings lead to a new series of questions pertaining to the pathogenic mechanisms of RTT. We propose to address them in the following specific aims: 1) To define the role of methyl-DNA binding of MeCP2 in the etiology of RTT-like phenotypes; 2) To dissect the role of MeCP2 in different neuronal cells regulating information processing; and 3) To investigate the molecular mechanisms by which MeCP2 modulates cell type-specific neuronal function. With the combined genetic, genomic, behavioral and neurophysiological approaches, we hope to not only reveal novel insight into the pathogenic mechanisms underlying RTT, but also to expedite the development of mechanism-based therapeutics that are focused on MeCP2 methyl-DNA binding and specific neuronal types. 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.