Between Slit and repulsion: Molecular mechanisms underlying Robo-mediated midline

狭缝与排斥之间：Robo 介导的中线的分子机制

• 批准号: 8290067
• 负责人: Rebecca Kent Chance
• 金额: $ 2.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290067
• 关键词: Affect; Attenuated; Autistic Disorder; Axon; Behavior; Biochemical; Biochemistry; Biological; Biological Assay; Biological Neural Networks; Cell Culture Techniques; Cell membrane; Cells; Cleaved cell; Communication; Complex; Cues; Data; Development; Disease; Drosophila genus; Dyslexia; Endocytosis; Event; Exclusion; Extracellular Domain; Family; Functional disorder; Genetic; Genetic Programming; Goals; Growth Cones; Health; Hereditary Disease; Human; Human Genetics; In Vitro; Individual; Injury; Instruction; Knowledge; Learning; Ligands; Light; Linguistics; Locomotion; Mediating; Metalloproteases; Molecular; Natural regeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Pattern; Peptide Hydrolases; Process; Proteolysis; Proteolytic Processing; Receptor Activation; Receptor Signaling; Regulation; Role; Schizophrenia; Series; Shapes; Signal Transduction; Site; Surface; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Variant; axon growth; axon guidance; behavior influence; design; extracellular; gamma secretase; gaze palsy; horizontal gaze; in vivo; insight; mutant; receptor; repaired; research study; response; scoliosis; spatiotemporal

Proper connectivity of the central nervous system allows for communication between hemispheres necessary for such diverse functions as locomotion and linguistic processing. A clear understanding of how an individual axon growth cone makes a guidance decision during development is necessary to learn how reproducible connectivity patterns are accomplished in normal development. Knowledge as to how axon guidance receptors convert extracellular cues into a guidance choice will be essential to serve the long-term goal of guiding rewiring in developmental disease, neurodegenerative disease or injury states. This proposal is designed to provide mechanistic insight into the how the regulation of signaling of one axon guidance receptor, Roundabout (Robo) affects its repulsive guidance instruction. Determining whether and how the spatiotemporal profile of activated Robo affects growth cone guidance is a largely unexplored topic and may provide insight into general mechanisms of guidance receptor regulation. The proposed experiments use Drosophila genetics, biochemistry, and cell culture approaches to test the hypothesis that ligand-dependent internalization of Robo, by proteolysis and endocytosis, regulates the spatiotemporal dynamics of signaling within a growth cone during repulsive guidance. Knowledge of the mechanism by which an activated receptor informs wiring decisions will provide insight into optimal points of therapeutic intervention in developmental diseases of miswiring and repair following injury or neurodegenerative disorder.

中枢神经系统的适当连接允许两个半球之间的交流，这是运动和语言处理等不同功能所必需的。清楚地了解个体轴突生长锥如何在发育过程中做出指导决定，对于了解可复制的连接模式是如何在正常发育中实现的是必要的。了解轴突引导受体如何将细胞外线索转化为引导选择，对于在发育疾病、神经退行性疾病或损伤状态下引导重新连接的长期目标至关重要。 这一建议旨在提供对一个轴突指导受体RoundAbout(Robo)的信号调节如何影响其排斥指导指令的机械性见解。确定被激活的Robo的时空分布是否以及如何影响生长锥引导在很大程度上是一个未被探索的话题，并可能为指导受体调节的一般机制提供洞察力。拟议的实验利用果蝇遗传学、生物化学和细胞培养方法来测试这一假说，即在排斥引导过程中，Robo的配体依赖的内化通过蛋白质分解和内吞调节生长锥内信号的时空动态。了解激活的受体通知连接决定的机制将为治疗发育疾病的最佳治疗干预点提供洞察，这些疾病包括连接错误和损伤后的修复或神经退行性疾病。