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: 7553537
• 负责人: ANIRVAN GHOSH
• 金额: $ 37.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7553537
• 关键词: Brain; CREB1 gene; Calcium; Calcium Signaling; Cell Survival; Development; Disruption; Gene Targeting; Genes; Genetic Transcription; Goals; Knowledge; Mediating; Molecular; Mus; Neurons; Pathway interactions; Proteins; Regulation; Role; Sensory; Synaptic plasticity; Transcriptional Activation; activating transcription factor; base; experience; insight; neural circuit; promoter; 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.

感觉体验通过激活神经回路来影响大脑发育。这些通路的激活导致神经元功能的各个方面的钙依赖调节，如突触可塑性、细胞存活、轴突和树突重塑。在大多数情况下，钙信号通过激活诱导目标基因表达的转录因子来发挥长期的细胞效应。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。 历史上，钙调节的转录因子是基于对靶基因的启动子分析来识别的，这种方法导致了功能上重要的转录因子的识别，如CREB。启动子分析方法虽然有效，但不适合于全面鉴定转录因子，特别是在目标基因未知的情况下。为了鉴定钙激活的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，可以在不事先知道靶基因的情况下克隆神经元中的钙激活的转录因子。通过这个筛选，我们发现bHLH蛋白Neuro-D2是一种钙激活的转录 因素。这项建议的目的是描述调控Neuro-D2介导的转录的分子机制，并基于对具有Neuro-D2基因靶向性干扰的小鼠的分析，评估Neuro-D2在皮质发育和可塑性中的作用。