Intra-axonal signaling pathways triggered by attractive guidance cues.

由有吸引力的引导线索触发的轴突内信号通路。

基本信息

批准号：
8644941
负责人：
Ulrich Hengst
金额：
$ 43.98万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644941
关键词：
1-Phosphatidylinositol 3-Kinase Actins Address Axon Behavior Biological Assay Brain Cell membrane Cell surface Characteristics Chemistry Co-Immunoprecipitations Code Complex Cues Cytoskeleton DNA Sequence Rearrangement Development Distal Dominant-Negative Mutation Ensure Etiology Event Exocytosis Fluorescence Genetic Translation Goals Growth Growth Cones Knowledge Literature Mediating Membrane Membrane Protein Traffic Mental disorders Messenger RNA Methods Microfluidics Microtubules Molecular Monomeric GTP-Binding Proteins Neurodevelopmental Disorder Neurons Pathology Pathway interactions Phospholipids Process Protein Biosynthesis Psyche structure Publishing Reporter Research Research Proposals Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Small Interfering RNA Stimulus Surface Synapses Testing Time Translations Vesicle axon growth axon guidance axonal pathfinding base design extracellular human NTN1 protein membrane model membrane synthesis nervous system development netrin-1 neurodevelopment neuronal cell body neuronal circuitry public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): During the development of the nervous system, axons are directed to their cognate synaptic targets by guidance factors that exert either a repulsive or an attractive effect onto axons and growth cones. Disturbances in the intricately regulated process of axonal pathfinding interfere with the establishment of correct synaptic connections and the formation of proper neuronal circuitry. Consequently, alterations of axonal pathfinding are thought to cause a wide variety of neurodevelopmental disorders. Netrin-1 and NGF are attractive guidance cues that induce faster growth rates in axons, as well as growth cone elaboration and attractive turning. These morphological changes are mediated by the rearrangement of the highly dynamic actin and microtubules cytoskeleton within growth cones, and a great amount of prior research has addressed the intra-axonal signaling pathways governing these cytoskeletal changes. However, besides cytoskeletal growth the process of axon elongation and growth cone elaboration requires the rapid, massive enlargement of the cell surface. The phospholipids that make up the nascent plasma membrane are anterogradely transported along the axons from the cell bodies in the form of plasma membrane precursor vesicles (PPVs). These PPVs fuse with the growth cone membrane thereby enlarging the surface of axons and growth cones in a regulated process called polarized exocytosis. Plasma membrane expansion and cytoskeletal dynamics have to occur at the same site and at the same time to achieve axon outgrowth or turning. Currently, it is unknown how this synchronicity between two seemingly separate pathways is established. The goal of this application is to understand how these two molecular pathways, cytoskeletal rearrangement and polarized exocytosis of PPVs, are integrated and co-regulated downstream of netrin-1 and NGF signaling to result in the characteristic axonal outgrowth and growth cone turning that characterize the morphological response of axons to attractive guidance cues. Based on preliminary studies, a special focus of this research proposal is to understand the functional significance of intra-axonal mRNA translation for the co-activation of both pathways. The successful completion of this research will provide a coherent view of the signaling cascades that ensure the temporal-spatial concurrence of cytoskeletal dynamics and membrane expansion within distal axons and growth cones stimulated with attractive guidance cues.

描述（由申请人提供）：在神经系统的开发过程中，轴突通过引导因素针对轴突和生长锥的指导因素针对其同源突触靶标的。轴突路径的复杂调节过程中的干扰会干扰正确的突触连接和形成正确的神经元电路。因此，轴突探索的改变被认为会导致多种神经发育障碍。 Netrin-1和NGF是有吸引力的指导线索，可诱导轴突的更快增长速度，以及生长锥阐述和有吸引力的转弯。这些形态学的变化是由高度动态肌动蛋白和生长锥中的微管细胞骨架的重排介导的，并且大量的先前研究已经解决了轴内信号传导途径，这些信号传导途径管理这些细胞骨架变化。但是，除了细胞骨架生长外，轴突伸长和生长锥体的过程还需要细胞表面的快速，大量扩大。构成新生质膜的磷脂是以质膜前体囊泡（PPV）的形式从细胞体沿轴突前进的。这些PPV与生长锥膜融合，从而在称为极化胞吐作用的受调节过程中扩大了轴突和生长锥的表面。质膜膨胀和细胞骨架动力学必须在同一部位和同时进行轴突生长或转弯。当前，尚不清楚如何建立两个看似独立的途径之间的这种同步性。该应用的目的是了解这两种分子途径，PPV的细胞骨架重排和极化胞吐作用如何集成并共同调节Netrin-1和NGF信号的下游，从而导致特征性的轴突差异和生长锥的特征，从而表征了轴突对轴突对有吸引力的指导的形式响应的响应。基于初步研究，该研究建议的特殊重点是了解轴内mRNA翻译在两种途径的共激活中的功能意义。这项研究的成功完成将为信号级联反应提供一致的视图，以确保通过有吸引力的指导提示刺激的远端轴突和远端轴突和生长锥体内的细胞骨架动力学和膜膨胀的颞空间并发。