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与RETT综合征（RTT）相关的MECP2的作用，该基因通过其作为转录抑制器的功能在兴奋性神经传递中。我们最近表明，神经元中MECP2的丧失有助于改变但不是抑制性突触传播的改变。我们还证明，由于MECP2作为转录阻遏物的作用，兴奋性传播中的这些缺陷似乎是短期可塑性的。相反，我们最近发现，MECP2的过表达会导致兴奋性突触传播和突触抑郁症的改变，与MECP2丢失后获得的突触抑郁症相反。这很重要，因为如果MECP2是突触功能的真正调节剂，那么我们希望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，细胞和电生理方法解决三个特定目标来补充和扩展我们以前的工作。首先，我们将进一步表征MECP2在短期可塑性中的丧失，以更完全辨别其在神经元功能中的内源性作用。其次，我们将在短期可塑性中表征MECP2的过表达，以检查MECP2表达效果突触传播的变化。这很重要，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基酶（HDACS）1和2，这是基因抑制的关键阻遏物，这是多蛋白质复合物与MECP2在调节基因表达中在突触传播中的一部分。我们的假设是MECP2表达的改变有助于对突触功能的影响。本应用程序中提出的研究将通过进一步表征MECP2表达的变化如何导致神经传递的缺陷以及MECP2复合物的HDAC成分如何参与这些过程中的HDAC成分，从而扩展了我们的原始假设。此信息很重要，因为它将开始提供一个框架，以探讨突触变化如何构成RTT方面的基础。公共卫生相关性：该项目中提出的实验代表了解决与Rett综合征相关的MECP2的综合努力，该基因通过其作为转录阻遏物的功能在兴奋性神经传递中。当前，缺乏对MECP2在中央突触中短期突触可塑性中的作用进行彻底分析。在这个项目中，我们将通过互补方法检查MECP2的丢失或MECP2的过表达如何有助于突触传播的改变。我们还将阐明组蛋白脱乙酰基酶（HDACS）1和2，这是基因抑制的关键抑制剂，这是多蛋白质复合物与MECP2在调节基因表达中的多蛋白络合物的一部分，对突触传递。从这些研究中获得的信息将提供有关RETT综合征可能影响的突触机制以及涉及MECP2表达改变的相关疾病的新见解。