MeCP2 Dependent Transcriptional Repression & Neurotransmission

MeCP2 依赖性转录抑制

• 批准号: 7620054
• 负责人: LISA M MONTEGGIA
• 金额: $ 35.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620054
• 关键词: Address; Affect; Area; Binding; Complement; Complex; Cytosine; Disease; Electrophysiology (science); Frequencies; Gait; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Grant; HDAC1 gene; HDAC2 gene; Hand; Hippocampus (Brain); Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Individual; Knock-out; Link; Mediating; Mental Retardation; Methods; Methyl-CpG-Binding Protein 2; Molecular; Movement; Multiprotein Complexes; Mus; Mutation; Neurodevelopmental Disorder; Neurologic; Neurons; Optical Methods; Patients; Pharmaceutical Preparations; Phenotype; Problem behavior; Process; Proteins; Regulation; Relative (related person); Rett Syndrome; Role; Symptoms; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Syndrome; Transcription Repressor/Corepressor; Work; disease-causing mutation; follow-up; gene repression; girls; insight; interest; male; neurotransmission; overexpression; promoter; public health relevance; research study; synaptic depression; synaptic function; synaptogenesis; trafficking; transmission process

DESCRIPTION (provided by applicant): The major objective of this proposal is to further delineate the role of MeCP2, the gene linked to Rett Syndrome (RTT), in excitatory neurotransmission through its function as a transcriptional repressor. We have recently shown that the loss of MeCP2 in neurons contributes to alterations in exicitatory, but not inhibitory, synaptic transmission. We also demonstrated that these deficits in excitatory transmission, a component of short term plasticity, appear due to MeCP2's role as a transcriptional repressor. Conversely we have recently found that overexpression of MeCP2 results in alterations in excitatory synaptic transmission and synaptic depression opposite to those obtained following the loss of MeCP2. This is important because if MeCP2 is a bona fide regulator of synaptic function then we would expect bidirectional changes in MeCP2 to result in reciprocal alterations in neurotransmission. The proposed studies will complement and extend our previous work by addressing three specific aims using molecular, cellular and electrophysiological methods. We will first, further characterize the loss of MeCP2 in short term plasticity to more fully discern its endogenous role in neuronal function. Second, we will characterize the overexpression of MeCP2 in short term plasticity to examine how alterations in MeCP2 expression effects synaptic transmission. This is important since recent studies have shown that duplication of the MeCP2 gene may underlie certain forms of mental retardation and progressive neurological symptoms. Lastly, we will elucidate the role of histone deacetylases (HDACs) 1 and 2, key repressors of gene repression that are part of a multiprotein complex with MeCP2 in regulating gene expression, on synaptic transmission. Our hypothesis is that alterations in MeCP2 expression contribute to effects on synaptic function. The studies proposed in this application will extend our original hypothesis by further characterizing how alterations in the expression of MeCP2 contributes to deficits in neurotransmission as well as how the HDAC components of the MeCP2 complex may be involved in these processes. This information is important because it will start to provide a framework in which to explore how synaptic alterations may underlie aspects of RTT. PUBLIC HEALTH RELEVANCE: The experiments proposed in this project represent a comprehensive effort to address the role of MeCP2, the gene linked to Rett Syndrome, in excitatory neurotransmission through its function as a transcriptional repressor. Currently, a thorough analysis of the role of MeCP2 in short-term synaptic plasticity in central synapses is lacking. In this project, we will examine via complementary approaches how the loss of MeCP2 or the overexpression of MeCP2 contributes to alterations in synaptic transmission. We will also elucidate the role of histone deacetylases (HDACs) 1 and 2, key repressors of gene repression that are part of a multiprotein complex with MeCP2 in regulating gene expression, on synaptic transmission. Information attained from these studies will provide new insight into the synaptic mechanisms that may be affected in Rett Syndrome as well as related disorders that involve alterations in MeCP2 expression.

描述（由申请人提供）：该提案的主要目的是进一步描述 MeCP2（与 Rett 综合征（RTT）相关的基因）通过其作为转录抑制因子的功能在兴奋性神经传递中的作用。我们最近发现，神经元中 MeCP2 的缺失会导致兴奋性突触传递的改变，但不会改变抑制性突触传递。我们还证明，兴奋性传递（短期可塑性的一个组成部分）的这些缺陷是由于 MeCP2 作为转录抑制因子的作用而出现的。相反，我们最近发现 MeCP2 的过度表达会导致兴奋性突触传递和突触抑制的改变，这与 MeCP2 缺失后所获得的改变相反。这很重要，因为如果 MeCP2 是突触功能的真正调节者，那么我们预计 MeCP2 的双向变化会导致神经传递的相互改变。拟议的研究将通过使用分子、细胞和电生理学方法解决三个具体目标来补充和扩展我们之前的工作。首先，我们将进一步表征 MeCP2 短期可塑性的丧失，以更全面地辨别其在神经元功能中的内源性作用。其次，我们将表征 MeCP2 的短期可塑性过度表达，以研究 MeCP2 表达的改变如何影响突触传递。这一点很重要，因为最近的研究表明 MeCP2 基因的重复可能是某些形式的智力低下和进行性神经系统症状的基础。最后，我们将阐明组蛋白脱乙酰酶 (HDAC) 1 和 2 的作用，它们是基因抑制的关键抑制因子，是与 MeCP2 形成的多蛋白复合物的一部分，在调节基因表达和突触传递中的作用。我们的假设是 MeCP2 表达的改变会影响突触功能。本申请中提出的研究将通过进一步表征 MeCP2 表达的改变如何导致神经传递缺陷以及 MeCP2 复合物的 HDAC 成分如何参与这些过程来扩展我们最初的假设。这些信息很重要，因为它将开始提供一个框架来探索突触改变如何成为 RTT 各个方面的基础。公共健康相关性：本项目提出的实验代表了一项全面的努力，旨在解决 MeCP2（与雷特综合征相关的基因）通过其作为转录抑制因子的功能在兴奋性神经传递中的作用。目前，缺乏对 MeCP2 在中央突触短期突触可塑性中的作用的全面分析。在这个项目中，我们将通过补充方法研究 MeCP2 的丢失或 MeCP2 的过度表达如何导致突触传递的改变。我们还将阐明组蛋白脱乙酰酶 (HDAC) 1 和 2 的作用，它们是基因抑制的关键抑制因子，是与 MeCP2 形成的多蛋白复合物的一部分，在调节基因表达和突触传递中的作用。从这些研究中获得的信息将为了解雷特综合征以及涉及 MeCP2 表达改变的相关疾病可能受影响的突触机制提供新的见解。