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，我们先前开发并表征了一个小鼠模型，该模型概括了RTT相关的错义突变MeCP2 T158A。我们发现，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。患有MeCP2功能障碍的小鼠也表现出与年龄相关的神经元事件相关电位(ERPs)受损，这表明神经回路被破坏。此外，我们正在进行的工作支持MeCP2以细胞类型特异性的方式在基因转录和树突状细胞发育中的调节作用。总之，这些发现导致了关于RTT致病机制的一系列新问题。我们建议在以下特定目标中解决这些问题：1)确定MeCP2的甲基DNA结合在RTT样表型的病因学中的作用；2)剖析MeCP2在不同神经细胞调节信息处理中的作用；以及3)研究MeCP2调节细胞类型特异性神经元功能的分子机制。结合遗传学、基因组学、行为学和神经生理学的方法，我们希望不仅揭示RTT的发病机制，而且加快以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的发展。此外，我们拟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。

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.