Slit Fragments Generate Diversity in Axon Guidance Signals

狭缝片段产生轴突引导信号的多样性

基本信息

批准号：
10392317
负责人：
Thomas Kidd
金额：
$ 39.58万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392317
关键词：
Address Adhesions Affect Alleles Antibodies Axon Binding Sites Biological Biological Assay Biological Process Blood Vessels Brain Cell Adhesion Cell Culture Techniques Cells Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Cues Data Development Down Syndrome Cell Adhesion Molecule Drosophila genus Embryo Experimental Models Goals Growth HIV In Vitro Knock-out Length Ligands Malignant Neoplasms Mediating Metabolic Molecular Molecular Genetics Mus Muscle fasciculation Nerve Nerve Regeneration Nervous system structure Neurons Outcome Output Peptide Hydrolases Permeability Phenotype Physiological Principal Investigator Process Production Proteins Proteolytic Processing Reagent Recombinant Proteins Role Sensory Signal Transduction Signaling Molecule System Testing Tissues Transgenic Organisms Work axon growth axon guidance base cell type design experimental study fly genetic approach genetic testing in vivo in vivo evaluation inhibitor mutant nervous system development neurodevelopment novel programs receptor receptor binding response tool

项目摘要

Axon guidance is the study of how developing nerves navigate in response to external signals. A remarkably small number of navigational signals have been identified, raising the question of how the complexity of the brain is generated. One solution is that a single ligand can signal in different ways either through the presence of different receptors or through processing that alters receptor binding. Slit is a large secreted protein that typically repels growing axons using Robo receptors. Slit is cleaved into two fragments, Slit-N and Slit-C, which display new biological activities in the nervous system and that in many other tissues. However, the role of the Slit fragments is controversial. The Slit-N fragment contains the Robo binding site and has been shown to be repel axons in in vitro culture systems and so is thought to be the active signaling molecule. Multiple lines of in vivo preliminary evidence in Drosophila suggest that only the full-length (Slit-FL) protein repels axons. This proposal takes an in vivo molecular genetic approach in flies and mice to separate the signaling of Slit-FL from that of the Slit fragments.These two systems will allow us to address the effects of Slit on axon growth, axon branching and regulated adhesion (fasciculation). This work will allow us to determine how a single signal can achieve different biological outcomes. The proposed work has implications for a diverse range of fields, including infectious disease, cancer and nerve regeneration.

轴突指导是研究神经如何响应外部的神经如何导航信号。已经确定了少量的导航信号，升高如何产生大脑复杂性的问题。一种解决方案是一个配体可以通过存在不同的受体或通过处理该改变受体结合。狭缝是一种大的分泌蛋白通常使用机器人受体排斥生长轴突。狭缝被切成两个碎片，裂隙-N和缝隙C，在神经系统中显示新的生物学活动，并在许多其他组织。但是，狭缝片段的作用是有争议的。狭缝-N 碎片包含机器人结合位点，已被证明是驱动轴突体外培养系统，因此被认为是活性信号分子。多行果蝇中体内初步证据表明只有全长（缝隙）蛋白质排斥轴突。该建议采用果蝇的体内分子遗传学方法和小鼠将狭缝-FL的信号与缝隙片段的信号分开。系统将使我们能够解决缝隙对轴突生长，轴突分支和调节的粘附（fasticulation）。这项工作将使我们能够确定一个单一的信号可以实现不同的生物学结果。拟议的工作对各种领域，包括传染病，癌症和神经再生。