The role of PRR7 in gene transcription and synaptic function

描述（由申请人提供）：摘要在神经元中基因表达的活性依赖性诱导中起作用的转录调节因子的突变与人类认知障碍密切相关。例如，Rett综合征和Rubenstein-Taybi综合征的发病机制分别由转录因子MeCP 2和转录共激活因子CBP的突变引起。然而，很少有人知道特定的基因表达模式是如何诱导神经元刺激。因此，鉴定调节活性依赖性基因表达的转录因子将指导用于开发人类认知障碍的疗法的更具选择性的策略。在这项提案中，我们将使用电生理学，分子遗传学和表观基因组学技术来测试的假设，即新的未表征的蛋白质PRR 7控制基因表达响应突触刺激，也调节突触功能。PRR 7是在筛选含有核定位序列（NLS）的突触后密度蛋白中鉴定的，以鉴定可用作突触到核信使的蛋白质。我们将通过检测缺乏和过表达PRR 7的培养神经元中的自发突触活动来确定PRR 7在突触功能中的作用。为了评估PRR 7作为转录因子的作用，我们将使用荧光素酶报告基因测定来测试其特异性结合DNA并激活基因转录的能力。通过本文所述的实验，我们将确定PRR 7是否是哺乳动物脑中神经元转录因子和突触功能调节因子。这项研究将增加我们对调节突触强度的转录因子的了解，这对正常的大脑功能至关重要。

DESCRIPTION (provided by applicant): ABSTRACT Mutations in transcription regulators that play a role in activity-dependent induction of gene expression in neurons are strongly linked to human cognitive disorders. For example, the pathogenesis of Rett-syndrome and Rubenstein-Taybi syndrome result from mutations in the transcription factor MeCP2 and the transcription co-activator CBP, respectively. However, little is known on how specific gene expression patterns are induced in response to neuronal stimulation. Therefore, an identification of the transcription factors that regulate activity dependent gene expression would guide more selective strategies for developing therapies for human cognitive disorders. In this proposal we will use electrophysiology, molecular genetics and Epigenomics techniques to test the hypothesis that the novel uncharacterized protein PRR7 controls gene expression in response to synaptic stimuli and also regulates synaptic function. PRR7 was identified in a screen for postsynaptic density proteins that contain a nuclear localization sequence (NLS) to identify proteins that could serve as synapse-to-nucleus messengers. We will determine the role of PRR7 in synaptic function by examining spontaneous synaptic activity in cultured neurons lacking and overexpressing PRR7. To evaluate the role of PRR7 as a transcription factor we will test its ability to bind specifically to DNA and activate gene transcription using a Luciferase reporter assay. With the experiments described here, we will determine if PRR7 is a neuronal transcription factor and a regulator of synaptic function in mammalian brain. This study will increase our knowledge of the transcription factors that regulate synaptic strength, which is essential for proper brain function.