Role of Neuro-D2 in Cortical Development and Plasticity

Neuro-D2 在皮质发育和可塑性中的作用

• 批准号: 6825162
• 负责人: ANIRVAN GHOSH
• 金额: $ 37.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-20 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825162
• 关键词: brain; brain cell; calcium flux; developmental neurobiology; experience; gene environment interaction; gene targeting; genetic transcription; genetically modified animals; immunoprecipitation; laboratory mouse; laboratory rat; microarray technology; neural plasticity; tissue /cell culture; transcription factor

Sensory experience influences brain development by by activating neural circuits. The activation of these pathways leads to calcium-dependent regulation of various aspects of neuronal function such as synaptic plasticity, cell survival, and axonal and dendritic remodeling. In most of these instances calcium signals exert long-lasting cellular effects by activating transcription factors that induce expression of target genes. Our overall goal is to gain insight into the mechanisms by which calcium signals influence brain development via transcriptional activation. Calcium-regulated transcription factors have historically been identified based on promoter analysis of target genes, and that approach has led to the identification of functionally important transcription factors such as CREB. The promoter analysis approach, while effective, is not suited for comprehensive identification of transcription factors, specially if the target genes are not known. To identify calcium-activated transcription factors and to evaluate their role in cortical development we have developed a new screen that can be used to clone calcium-activated transcription factors in neurons without prior knowledge of the target genes. Using this screen we have discovered that the bHLH protein Neuro-D2 is a calcium-activated transcription factor. The aims of this proposal are to characterize the molecular mechanisms that regulate Neuro-D2-mediated transcription, and to evaluate the role of Neuro-D2 in cortical development and plasticity based on analysis of mice that have a targeted disruption of the Neuro-D2 gene.

感官体验通过激活神经回路影响大脑发育。这些途径的激活导致神经元功能各个方面的钙依赖性调节，例如突触可塑性、细胞存活以及轴突和树突重塑。在大多数情况下，钙信号通过激活诱导靶基因表达的转录因子来发挥持久的细胞效应。我们的总体目标是深入了解钙信号通过转录激活影响大脑发育的机制。 钙调节转录因子历来是根据靶基因的启动子分析来鉴定的，这种方法已经导致了功能上重要的转录因子（例如 CREB）的鉴定。启动子分析方法虽然有效，但不适合转录因子的全面鉴定，特别是在靶基因未知的情况下。为了鉴定钙激活转录因子并评估它们在皮质发育中的作用，我们开发了一种新的筛选方法，可用于在事先不了解目标基因的情况下克隆神经元中的钙激活转录因子。通过这个筛选，我们发现 bHLH 蛋白 Neuro-D2 是一种钙激活转录 因素。该提案的目的是表征调节 Neuro-D2 介导的转录的分子机制，并基于对 Neuro-D2 基因有针对性破坏的小鼠的分析来评估 Neuro-D2 在皮质发育和可塑性中的作用。