Understanding the Pathogenic Mechanisms of Rett Syndrome

描述（由申请人提供）：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，我们以前开发和表征了一种小鼠模型，重现了RTT相关的错义突变MeCP 2 T158 A。我们发现，T158 A突变小鼠表现出类似的RTT样表型的Mecp 2-null小鼠。T158 A突变降低了MeCP 2与甲基化DNA的结合，并降低了MeCP 2蛋白的稳定性。MeCP 2功能障碍的小鼠还显示出神经元事件相关电位（ERP）的年龄依赖性损伤，指示神经回路中断。此外，我们正在进行的工作支持MeCP 2在细胞类型特异性方式中调节基因转录和树突发育中的作用。总之，这些发现导致了一系列新的问题，有关RTT的致病机制。我们提出解决他们在以下具体目标：1）确定甲基DNA结合的MeCP 2的RTT样表型的病因学中的作用; 2）解剖的作用，MeCP 2在不同的神经元细胞调节信息处理;和3）调查的分子机制，MeCP 2调节细胞类型特异性神经元功能。通过结合遗传学、基因组学、行为学和神经生理学方法，我们希望不仅能揭示RTT致病机制的新见解，还能加快基于机制的治疗方法的发展，这些治疗方法专注于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，以调查各种生物过程和疾病的表观遗传机制。

DESCRIPTION (provided by applicant): 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.