Role of MeCP2 in Circuitry Development and Plasticity

MeCP2 在电路发育和可塑性中的作用

基本信息

批准号：
8758660
负责人：
Qizhi Gong
金额：
$ 32.29万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8758660
关键词：
Adult Alleles Antibodies Apical Axon Behavior Binding Biological Models Brain Candidate Disease Gene Cell Adhesion Molecules Characteristics Cognitive CpG Islands CpG dinucleotide DNA Binding Defect Dendrites Development Etiology Future Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Goals Health Internal Ribosome Entry Site Knockout Mice Knowledge Label Lentivirus Vector Mediating Methyl-CpG-Binding Protein 2 Modeling Morphology Mus Mutation Nasal cavity Nervous system structure Neuraxis Neurodevelopmental Disorder Neuronal Plasticity Neurons Odorant Receptors Olfactory Epithelium Olfactory Pathways Phenotype Phosphorylation Physiological Play Population Presynaptic Terminals Process Receptor Gene Regulation Rett Syndrome Reverse Transcriptase Polymerase Chain Reaction Role Site Testing Tissues Transcriptional Regulation cell type chromatin immunoprecipitation density differential expression gene function insight knockout gene lentiviral-mediated mitral cell mouse genome olfactory bulb olfactory sensory neurons postnatal presynaptic promoter receptor expression research study synaptogenesis therapeutic development therapy design

项目摘要

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.

描述（由申请人提供）：RETT综合征是由甲基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中神经元成熟，突触发生和树突发展的缺陷。 MECP2是一种转录调节剂，优先与甲基化的CpG二核苷酸序列结合。 MECP2靶基因的识别及其在功能电路的建立中的功能对于未来的治疗方法开发至关重要。几种独特的特征使脊椎动物嗅觉系统成为研究MECP2功能的绝佳模型。 1）。嗅觉感觉神经元是嗅觉上皮中的唯一神经元类型。这将促进转录法规的识别，而不会干扰混合的调节作用，而这些调节作用在皮质组织的混合神经元种群中可见。 2）复杂和精确的嗅觉连接允许识别轴突从其特定的嗅球灶中识别。 3）由于鼻腔中嗅觉感觉神经元的可及性，可以轻松地在生理水平上操纵神经元活性。这项研究的目的是将嗅觉系统用作模型，以进一步定义电路形成和改进中的MECP2功能。在AIM 1中，我们将检验以下假设：形成精确的成年嗅觉连接所必需的MECP2。在AIM 2中，我们将检验以下假设：MECP2调节嗅觉感觉神经元中细胞粘附分子的表达。在AIM 3中，我们将检验以下假设：MECP2调节嗅觉系统中活性调节细胞粘附分子的转录。通过这项研究，我们希望不仅在嗅觉系统中，而且在中枢神经系统的其他区域中更好地了解MECP2功能。