Role of MeCP2 in Circuitry Development and Plasticity

描述(申请人提供)：Rett综合征是一种由甲基CpG结合蛋白2基因(MeCP2)突变引起的神经发育障碍。MeCP2功能的丧失导致中枢神经系统神经元成熟、突触发生和树突发育的缺陷。MeCP2是一种转录调节因子，优先与甲基化的CpG二核苷酸序列结合。识别MeCP2靶基因并了解它们在建立功能电路中的功能对于未来治疗方法的发展至关重要。脊椎动物嗅觉系统的几个独特特征使其成为研究MeCP2功能的极佳模型。1)。嗅觉神经元是嗅觉上皮中唯一的神经元类型。这将有助于在没有混合调节效应的情况下识别转录调节，而混合调节效应在皮质组织的混合神经元群体中可见。2)复杂而精确的嗅觉连接可以识别出轴突错误地定位于其特定的嗅球焦点。3)由于鼻腔内嗅觉感觉神经元的可达性，在生理水平上很容易实现对神经元活动的操纵。本研究的目的是以嗅觉系统为模型，进一步明确MeCP2在回路形成和精化中的作用。在目标1中，我们将检验这一假设，即MeCP2是形成精确的成人嗅觉连接所必需的。在目标2中，我们将检验MeCP2调节嗅觉感觉神经元细胞黏附分子表达的假设。在目标3中，我们将测试MeCP2调节嗅觉系统中活性调节的细胞黏附分子转录的假设。通过这项研究，我们希望更好地了解MeCP2不仅在嗅觉系统中的功能，而且在中枢神经系统的其他区域中的功能。 公共卫生相关性：本研究旨在确定MeCP2的靶基因，并以小鼠嗅觉系统为模型研究MeCP2的功能。了解MeCP2在嗅觉连接形成中的作用不仅有助于我们对大脑发育的基本了解，还将为Rett综合征的干预措施的设计提供见解。

DESCRIPTION (provided by applicant): Rett syndrome is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 gene (Mecp2). Loss of Mecp2 function results in defects in neuronal maturation, synaptogenesis and dendritic development in the central nervous system. MeCP2 is a transcription regulator that binds preferentially to methylated CpG dinucleotides sequences. Identification of MeCP2 target genes and understanding their functions in the establishment of functional circuitry is critical for future development of therapeutic approaches. Several unique characteristics make the vertebrate olfactory system an excellent model to study MeCP2 function. 1). Olfactory sensory neurons are the sole neuronal type in the olfactory epithelium. This will facilitate the identification of transcription regulations without the interference of mixed regulatory effects that are seen in mixed neuronal populations of cortical tissue. 2) The intricate and precise olfactory connections allow identification of axon mistargeting out of their specific olfactory bulb foci. 3) Manipulation of neuronal activity at the physiological level can be easily achieved due to the accessibility of olfactory sensory neurons in the nasal cavity. The goal of this study is to use the olfactory system as a model to further define MeCP2 function in circuitry formation and refinement. In Aim 1, we will test the hypothesis that MeCP2 is required for the formation of precise adult olfactory connections. In Aim 2, we will test the hypothesis that MeCP2 regulates expression of cell adhesion molecules in olfactory sensory neurons. In Aim 3, we will test the hypothesis that MeCP2 tunes transcription of activity-regulated cell adhesion molecules in the olfactory system. Through this study, we hope to gain better understanding of MeCP2 function not only in the olfactory system but also in other regions of the central nervous system. PUBLIC HEALTH RELEVANCE: This study aims to identify target genes of MeCP2 and investigate MeCP2 function using the mouse olfactory system as a model. Understanding MeCP2 function in the formation of olfactory connections will not only contribute to our basic understanding of brain development but also provide insights toward the design of interventions for Rett syndrome.