Molecular mechanisms of neuron motility and axon guidance

神经元运动和轴突引导的分子机制

• 批准号: 10626674
• 负责人: John G Flanagan
• 金额: $ 42.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626674
• 关键词: ASD patient; Accounting; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Axon; Basement membrane; Behavior; Biological; Biological Models; Biological Process; Biology; Brain; Cerebral cortex; Complex; Defect; Development; Dimerization; Disease; Distal; Elements; Exons; Family; Floor; Funding; Funding Agency; Gatekeeping; Genetic Translation; Goals; Grant; In Vitro; Instruction; Laminin; Lead; Ligand Binding; Ligands; Maps; Mediating; Messenger RNA; Modeling; Molecular; Mus; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurodevelopmental Disorder; Neurons; Pathogenicity; Pathway interactions; Pattern; Phase; Phosphorylation; Phosphorylation Site; Process; Protein Biosynthesis; Protein Region; Proteins; RNA; RNA-Binding Proteins; Radial; Regulation; Role; Signal Pathway; Signal Transduction; Source; Spinal; Spinal Cord; System; Testing; Therapeutic Intervention; Time; Translations; Up-Regulation; Work; autism spectrum disorder; axon guidance; base; cell motility; extracellular; gene network; genome-wide; genome-wide analysis; in vivo; insight; interest; migration; nervous system development; neurodevelopment; neuronal patterning; novel; operation; receptor; risk variant

The brain relies for its function on a precise and complex pattern of neuronal connections. The broad long-term goal of this project is to understand molecular mechanisms that set up this pattern of connections during development, and how aberrations of this process lead to neurodevelopmental disorders. This proposal focuses particularly on RNA-based regulatory mechanisms. Key advantages of regulating mRNA translation via RNA-binding proteins (RBPs) are: (1) allowing protein synthesis to be locally regulated in specific subcellular regions where the proteins are needed, and (2) coordinately regulating expression of large networks of functionally related mRNAs. To understand the basic principles of axon guidance, a major model system has been spinal commissural axon guidance at the midline. Navigating this intermediate target requires axons to be attracted and then repelled, and the classic mechanism for this is the `Robo switch' where repellent Robo receptors are upregulated in post-crossing axons; however, the extracellular signal and the mechanism by which it triggers this switch have been unknown. We have now identified a highly novel mechanism for the Robo switch, involving extracellular ligand binding to the transmembrane Amyloid Precursor Protein (APP), which interacts with the RBP CPEB4, to regulate Robo local translation in post-crossing axon segments. This novel APP-CPEB4 pathway has high relevance to disease: in addition to the role of APP in neurodegeneration, CPEB4 is currently of high interest as a cause of Autism Spectrum Disorder (ASD). The proposed studies continue our work on CPEB4, studying it in two developmental systems: (1) Spinal commissural axon midline guidance. Expression of many proteins is known to be locally regulated in axon segments at the midline, and the novel APP-CPEB4 pathway is likely to regulate not only Robo but other proteins. This work is expected to show coordinate regulation of a large gene network at an intermediate target, bringing together many disparate past observations into a unifying model for this major paradigm of axon guidance. (2) Radially migrating neurons in the cerebral cortex. Abnormalities in this phase of development are believed to be a leading cause of ASD. Based on existing evidence, CPEB4 regulates Robo expression in developing cortex, and CPEB4 conditional disruption in mouse cortex at this specific stage causes ASD-like behaviors. Compared to commissural axons, evidence indicates that CPEB4 regulates different processes in cortical development. Studies of CPEB4 in cortical development will therefore uncover novel biological principles, and will also directly inform the understanding of pathogenic mechanisms for ASD and other neurodevelopmental disorders. Approaches include genome-wide target mRNA identification, and functional developmental studies in vitro and in vivo. Additionally, studies of signal transduction mechanisms in the novel APP-CPEB4 pathway will be essential to understand its operation and long-term potential for therapeutic intervention, not only in the neurodevelopmental context but also in other systems in biology and disease.

大脑的功能依赖于神经元连接的精确而复杂的模式。长期的 该项目的目标是了解建立这种连接模式的分子机制 发展以及该过程的畸变如何导致神经发育障碍。 该提案特别关注基于RNA的调节机制。监管的关键优势 通过RNA结合蛋白（RBP）的mRNA翻译为：（1）允许蛋白质合成在局部调节 需要蛋白质的特定亚细胞区域，以及（2）协调调节大的表达 功能相关的mRNA网络。要了解Axon Guidance的基本原理，这是一个主要模型 系统是中线的脊柱轴突指导。导航此中间目标需要 要吸引然后排斥的轴突，而经典的机制是“机器人开关” 驱虫式的机器人受体在横断后轴突中上调。但是，细胞外信号和 触发此开关的机制尚不清楚。我们现在已经确定了一个非常新颖的 机器人开关的机理，涉及细胞外配体与跨膜淀粉样前体结合 与RBP CPEB4相互作用的蛋白质（APP），以调节后轴突中的Robo局部翻译 细分市场。这种新颖的App-CPEB4途径与疾病具有很高的相关性：除了应用在 神经变性，CPEB4目前引起了自闭症谱系障碍（ASD）的兴趣。 拟议的研究继续我们在CPEB4上进行研究，并在两个发展系统中进行了研究：（1） 脊柱连合轴突中线指导。已知许多蛋白质的表达在局部调节 中线的轴突段，而新颖的App-CPEB4途径不仅可以调节机器人，而且可以调节其他 蛋白质。预计这项工作将显示在中间目标处的大基因网络的坐标调节， 将许多不同的过去观察结果汇总到这个主要轴突范式的统一模型中 指导。 （2）在大脑皮层中径向迁移的神经元。在这一发展阶段的异常是 被认为是ASD的主要原因。根据现有证据，CPEB4调节机器人表达 在此特定阶段，在小鼠皮层中开发皮层和CPEB4有条件破坏会导致ASD样 行为。与合理轴突相比，证据表明CPEB4调节不同的过程 皮质发育。因此，CPEB4在皮质发育中的研究将发现新的生物学 原则，还将直接告知对ASD和其他ASD的致病机制的理解 神经发育障碍。方法包括全基因组目标mRNA识别和功能 体外和体内的发展研究。另外，对新颖的信号转导机制的研究 App-CPEB4途径对于了解其运行和长期治疗潜力至关重要 干预不仅在神经发育环境中，而且在生物学和疾病的其他系统中。