Understanding the Pathogenic Mechanisms of Rett Syndrome

描述（由申请人提供）：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，我们之前建立了一个小鼠模型，再现了RTT相关的错义突变MeCP2 T158A。我们发现携带T158A突变的小鼠表现出与mecp2缺失小鼠相似的rtt样表型。T158A突变降低了MeCP2与甲基化DNA的结合，降低了MeCP2蛋白的稳定性。MeCP2功能障碍小鼠也表现出神经元事件相关电位（ERPs）的年龄依赖性损伤，表明神经回路受损。此外，我们正在进行的工作支持MeCP2在以细胞类型特异性方式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关于RTT致病机制的新问题。我们提出解决这些问题的具体目标如下：1)确定MeCP2甲基dna结合在rtt样表型病因学中的作用；2)剖析MeCP2在不同神经元细胞调节信息加工中的作用；3)探讨MeCP2调控细胞特异性神经元功能的分子机制。通过结合遗传学、基因组学、行为学和神经生理学的方法，我们希望不仅能揭示RTT发病机制的新见解，而且还能加快以MeCP2甲基dna结合和特定神经元类型为重点的基于机制的治疗方法的发展。此外，我们提出的研究将为研究界提供创新的工具和资源，以研究各种生物过程和疾病背后的表观遗传机制。

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.