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Proto-oncogenes in Axon Guidance

轴突引导中的原癌基因

基本信息

批准号：
7414724
负责人：
SAMUEL L. PFAFF
金额：
$ 41.89万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7414724
关键词：
Address Afferent Neurons Afferent Pathways Amyotrophic Lateral Sclerosis Antibodies Axon Biochemical Biochemistry Biological Assay Brain Cells Chimeric Proteins Coculture Techniques Code Cues Data Defect Dermomyotome Development Efferent Pathways Embryo Ephrin-A5 Exhibits Exposure to Family Family suidae Generic Drugs Grant Growth Cones Healthcare Human In Situ Hybridization In Vitro Individual Knockout Mice Label LacZ Genes Ligand Binding Ligands Limb Bud Limb structure Mammals Masks Mediating Membrane Molecular Motor Motor Neuron Disease Motor Neurons Movement Mus Muscle Mutant Strains Mice Nervous system structure Neural tube Neurons Pathway interactions Pattern Phenotype Phosphotransferases Protein Isoforms Proteins Proto-Oncogenes RNA Splicing Receptor Cross-Talk Receptor Protein-Tyrosine Kinases Regulation Reporter Research Personnel Respiration Role Screening procedure Sensory Signal Transduction Site Small Interfering RNA Specificity Staining method Stains Sus scrofa System Testing Thinking Tissues Transgenic Mice axon guidance base cell motility crosslink in vivo insight interest mutant netrin-G1 novel preference promoter protein function receptor receptor expression research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): This grant proposes to study how embryonic motor neuron axons are guided to their appropriate muscle targets. These cells directly mediate the nervous system's control of respiration and movement. Thus, diseases of motor neurons such as ALS and SMA have devastating consequences for human health and care. Our studies should provide insight into how these cells develop and over the long term contribute to our general understanding of the mechanisms that control neuronal connectivity and circuit formation in the brain. During development, motor neuron subtypes are generated that exhibit distinct cell migration patterns and specific preferences for axon pathways. Although families of transcription factors have been identified in motor neuron subtypes, less is known about the molecular signals that control the connectivity of individual motor neuron subtypes in mammals. Our preliminary studies have implicated a family of receptor tyrosine kinases in axonal navigation, which others have found are proto-oncogenes in non-neuronal tissues. In aim 1 we will characterize how EphA and ephrin-A signaling is used to guide both MMCm and LMCI cells. These studies will help to understand how axon guidance molecules expand their repertoire of functions. In aim 2 we will examine inter-axonal interactions between motor and sensory neurons to understand how proper afferent and efferent pathways develop, focusing on the role of EphAs and ephrin-As present on motor and sensory neuron axons. In aim 3 we will characterize the role of FgfR1 in MMCm motor neuron axon guidance and study FgfR1-EphA4 receptor "cross-talk". This will help to understand how attractive and repulsive guidance cues are integrated by MMCm growth cones. In aim 4 we will identify coreceptors needed for reverse signaling by the ephrin-A GPI-anchored proteins and determine whether other GPI-anchored proteins function as motor axon guidance molecules.

描述（由申请人提供）：这项资助旨在研究胚胎运动神经元轴突如何被引导到适当的肌肉目标。这些细胞直接调节神经系统对呼吸和运动的控制。因此，运动神经元疾病，如ALS和SMA，对人类的健康和护理具有毁灭性的后果。我们的研究应该提供这些细胞如何发育的见解，并在长期内有助于我们对控制大脑中神经元连接和回路形成的机制的一般理解。在发育过程中，产生的运动神经元亚型表现出不同的细胞迁移模式和对轴突通路的特定偏好。虽然在运动神经元亚型中已经确定了转录因子家族，但对哺乳动物中控制单个运动神经元亚型连通性的分子信号知之甚少。我们的初步研究暗示了一个受体酪氨酸激酶家族在轴突导航中，其他人已经发现它是非神经元组织中的原癌基因。在目标1中，我们将描述如何利用EphA和ephrin-A信号传导来引导MMCm和LMCI细胞。这些研究将有助于理解轴突引导分子如何扩展其功能。在目标2中，我们将研究运动和感觉神经元之间的轴突间相互作用，以了解正确的传入和传出通路是如何发展的，重点是EphAs和ephrin- a在运动和感觉神经元轴突上的作用。在aim 3中，我们将描述FgfR1在MMCm运动神经元轴突引导中的作用，并研究FgfR1- epha4受体“串扰”。这将有助于理解MMCm生长锥是如何整合吸引和排斥引导信号的。在目标4中，我们将鉴定ephrin-A gpi锚定蛋白的反向信号所需的辅助受体，并确定其他gpi锚定蛋白是否具有运动轴突引导分子的功能。