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.

大脑的功能依赖于一种精确而复杂的神经元连接模式。宽泛的长期 这个项目的目标是了解在生命周期中建立这种连接模式的分子机制 以及这一过程的异常如何导致神经发育障碍。 该提案特别侧重于基于RNA的调控机制。监管的主要优势 通过RNA结合蛋白(RBP)进行的mRNA翻译：(1)允许蛋白质合成在局部受到调节 需要蛋白质的特定亚细胞区域，以及(2)协调调节大分子的表达 功能相关的mRNAs网络。要了解轴突引导的基本原理，一个主要的模型 系统已将脊髓连合轴突引导在中线。导航此中间目标需要 轴突被吸引然后被排斥，这方面的经典机制是‘机器人开关’，其中 排斥的Robo受体在交叉后轴突中上调；然而，细胞外信号和 它触发这种开关的机制尚不清楚。我们现在已经确定了一部高度小说 Robo开关的机制，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)调节交叉轴突后Robo的局部翻译 细分市场。这种新的APP-CPEB4通路与疾病有很高的相关性：除了APP在 神经退行性变，CPEB4是目前引起自闭症谱系障碍(ASD)的一个重要原因。 拟议的研究继续了我们关于CPEB4的工作，在两个发展系统中进行了研究：(1) 脊髓连合轴突中线引导。已知许多蛋白质的表达受局部调控。 轴突位于中线，新的APP-CPEB4通路可能不仅调节Robo，而且还调节其他 蛋白质。这项工作有望展示一个大的基因网络在一个中间目标上的协调调节， 将许多不同的过去观察结果结合到一个关于轴突的主要范式的统一模型中 指导。(2)大脑皮层内的放射状迁移神经元。这一发展阶段的异常情况是 被认为是ASD的主要原因。根据现有证据，CPEB4调控ROBO在脑内的表达 发育中的皮质，而在此特定阶段小鼠皮质中CPEB4的条件性破坏会导致ASD样 行为。与连合轴突相比，证据表明CPEB4调节不同的过程。 皮质发育。因此，对CPEB4在皮质发育中的研究将发现新的生物学 原理，并将直接有助于了解ASD和其他疾病的发病机制 神经发育障碍。方法包括全基因组靶向信使核糖核酸鉴定和功能 体外和体内发育研究。此外，对小说中的信号转导机制进行了研究 APP-CPEB4通路对于了解APP-CPEB4的操作和治疗的长期潜力是必不可少的 干预，不仅在神经发育背景下，而且在生物学和疾病的其他系统中。