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：
10052470
负责人：
Thomas Kidd
金额：
$ 40.82万
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/10052470
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 Cleaved cell 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/antagonist 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.

轴突引导是研究发育中的神经如何响应外部信息而导航的信号。已识别出极少量的导航信号，大脑的复杂性是如何产生的问题。一种解决方案是单个配体可以通过不同受体的存在或以不同方式发出信号通过改变受体结合的处理。狭缝是一种大型分泌蛋白通常使用 Robo 受体来排斥正在生长的轴突。狭缝被劈成两块， Slit-N 和 Slit-C，在神经系统和神经系统中显示出新的生物活性许多其他组织。然而，狭缝碎片的作用是有争议的。狭缝-N 片段包含 Robo 结合位点，并已被证明可以排斥轴突因此被认为是体外培养系统中的活性信号分子。多条线路果蝇体内初步证据表明，只有全长（Slit-FL）蛋白质排斥轴突。该提案采用果蝇体内分子遗传学方法和小鼠将 Slit-FL 的信号传导与 Slit 片段的信号分离。这两个系统将使我们能够解决 Slit 对轴突生长、轴突分支和调节粘附（束颤）。这项工作将使我们能够确定单个信号可以实现不同的生物学结果。拟议的工作对以下方面有影响：广泛的领域，包括传染病、癌症和神经再生。