Regulation of protein targeting in axon guidance and neuronal morphogenesis

轴突引导和神经元形态发生中蛋白质靶向的调节

基本信息

批准号：
9069619
负责人：
MARY C HALLORAN
金额：
$ 32.73万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069619
关键词：
Afferent Neurons Alzheimer&apos s Disease Axon Axonal Transport Behavior Binding Biosensor Carrier Proteins Cell membrane Cells Charcot-Marie-Tooth Disease Complex Cues Data Defect Dendrites Development Disease Dynein ATPase Embryo Endosomes Environment Event Goals Health Human Image Individual Kinesin Label Learning Life Ligands Link Location Maintenance Mediating Mediator of activation protein Membrane Membrane Protein Traffic Memory Microtubules Modeling Molecular Molecular Target Morphogenesis Morphology Motor Natural regeneration Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 3 Neurotrophin 3 Niemann-Pick Diseases PHluorin Pain Disorder Peripheral Process Protein Family Proteins Regulation Role Route Semaphorin-3A Semaphorins Sensory Signal Transduction Slide Structure System Testing Time Vesicle Vesicle Transport Pathway Zebrafish axon growth axon guidance axon injury extracellular in vivo in vivo Model knock-down mutant neural circuit neuron development neuronal transport neurotrophic factor novel painful neuropathy polymerization protein function protein transport receptor research study response synaptogenesis targeted imaging temporal measurement trafficking

项目摘要

DESCRIPTION (provided by applicant): Proper development of neuronal morphology and neural circuits, as well as neuronal maintenance, requires tightly controlled subcellular localization of proteins such as axon guidance cue receptors. Proteins are targeted to specific cell locations by elaborate membrane trafficking and axonal transport systems. Neurons are particularly dependent on high fidelity protein trafficking because of their highly polarized and complex structure. Defects in trafficking and transport underlie multiple human developmental and neurodegenerative diseases, including Alzheimer's disease, Charcot-Marie-Tooth, and Niemann Pick disease. Despite their importance, the mechanisms regulating trafficking processes in neurons are poorly understood, in part due to a paucity of in vivo models in which the machinery and mechanisms of axon transport can be studied. A major challenge to the field and the long term goal of this project is to understand the mechanisms controlling axonal transport and protein localization as neurons develop in their natural environment, where they must integrate multiple extracellular cues. We established a model in which we can image dynamics of neuronal cargo transport, protein localization, and microtubule behavior in the intact zebrafish embryo. Vertebrate sensory neurons extend distinct central and peripheral axons to form the sensory circuit. We found that these axons show distinct responses to axon guidance cues. Moreover, we discovered roles for endosomal trafficking and the kinesin adaptor Calsyntenin-1 (Clstn-1) in differential guidance of sensory axons. In Aim 1 we propose to determine how calsyntenins regulate endosome transport routes to different axon compartments. In Aim 2 we will investigate mechanisms regulating specific localization of receptors for Neurotrophin-3 and Semaphorin3d. We will test the hypothesis that Calsyntenins and another class of kinesin adaptors, the Collapsin response mediator proteins (CRMPs) function to target receptors to specific axon compartments. In Aim 3 we will determine how Clstn-1 and CRMPs organize microtubule polarity and dynamics, processes essential for accurate trafficking and axon growth. Our unique model allows us to connect the molecular events of axonal transport, guidance receptor localization and microtubule organization to specific axon guidance decisions at the time and place they naturally occur. Elucidation of the molecular signals regulating sensory axon growth, guidance, and protein trafficking is critical for understanding neurodegenerative disorders, neuropathic pain disorders and the conditions under which regeneration after axon injury can occur. Our experiments will uncover such mechanisms and thus may help to identify molecular targets for disease treatment.

描述（由申请人提供）：神经形态和神经回路的正确发育以及神经维持需要严格控制蛋白质的亚细胞定位，例如轴突引导信号受体蛋白质通过精心设计的膜运输和轴突运输靶向特定的细胞位置。神经元特别依赖于高保真蛋白质运输，因为其高度极化和复杂的结构是多种人类发育和神经退行性疾病的基础，包括阿尔茨海默病、尽管神经元运输过程的调节机制很重要，但人们对其知之甚少，部分原因是缺乏可以研究轴突运输机制和机制的体内模型。该领域的主要挑战和该项目的长期目标是了解神经元在自然环境中发育时控制轴突运输和蛋白质定位的机制，其中它们必须整合多种细胞外线索，我们建立了一个可以对动态进行成像的模型。神经元货物完整斑马鱼胚胎中的运输、蛋白质定位和微管行为延伸出不同的中枢和外周轴突以形成感觉回路。此外，我们还发现了内体运输的作用。和驱动蛋白接头 Calsyntenin-1 (Clstn-1) 在感觉轴突差异引导中的作用在目标 1 中，我们建议确定 Calsyntenin 如何调节内体运输路线。在目标 2 中，我们将研究调节 Neurotropin-3 和 Semaphorin3d 受体特异性定位的机制，我们将测试 Calsyntenins 和另一类驱动蛋白接头，即 Collapsin 反应介导蛋白 (CRMP) 对目标受体发挥作用的假设。在目标 3 中，我们将确定 Clstn-1 和 CRMP 如何调节微管极性和组织动态，以及准确运输所必需的过程。我们独特的模型使我们能够将轴突运输、引导受体定位和微管组织的分子事件与它们自然发生的时间和地点的特定轴突引导决策联系起来。蛋白质运输对于了解神经退行性疾病、神经性疼痛疾病以及轴突损伤后再生的条件，我们的实验将揭示这些机制，从而可能有助于确定疾病治疗的分子靶标。