Understanding the Pathogenic Mechanisms of Rett Syndrome

标题 对Rett综合征发病机制的认识 摘要 甲基CpG结合蛋白2(MECP2)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 重述与RTT相关的错义突变MeCP2 T158A的小鼠模型。我们发现老鼠 带有T158A突变的小鼠表现出与MeCP2缺失小鼠相似的RTT样表型。T158A突变 减少MeCP2与甲基化DNA的结合，降低MeCP2蛋白的稳定性。小鼠带有 MeCP2功能障碍也显示出神经元事件相关电位(ERPs)的年龄相关性损害 表明神经回路中断。此外，我们正在进行的工作支持MeCP2在 基因转录的调控和树突状细胞类型特异性的发育。一起， 这些发现引发了关于RTT致病机制的一系列新问题。我们 建议在以下具体目标中解决这些问题：1)界定甲基DNA结合的作用 MeCP2在RTT样表型病因学中的作用；2)剖析MeCP2在不同神经元中的作用 细胞调节信息处理；以及3)研究其分子机制。 MeCP2调节特定细胞类型的神经元功能。结合了遗传、基因组、行为 和神经生理学方法，我们希望不仅揭示致病机理的新见解 RTT的基础机制，但也要加快基于机制的疗法的发展， 主要集中在MeCP2甲基DNA结合和特定的神经元类型。此外，我们建议的研究 将为广大研究界提供创新的工具和资源，以调查 各种生物过程和疾病背后的表观遗传机制。

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.