Understanding the Multifunctionality of TAG-1 in Motor Neuron Development

了解 TAG-1 在运动神经元发育中的多功能性

基本信息

批准号：
9310055
负责人：
Tracey Amelia Claire Sampath Suter
金额：
$ 4.4万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310055
关键词：
Address Adhesions Afferent Neurons Alleles Alpha Cell Axon Biological Assay Cell Adhesion Cell Adhesion Molecules Cell Lineage Cells Cues Data Defect Development Diagnosis Disease Electron Microscopy Embryo Fascicle Future Genetic Glycoproteins Image Immunohistochemistry In Vitro Injury Invaded Knock-out Knockout Mice Knowledge Mediating Modeling Molecular Molecular Profiling Motor Motor Neurons Movement Mus Muscle Muscle fasciculation Nerve Degeneration Nervous System Trauma Nervous system structure Neuraxis Neurodegenerative Disorders Neuronal Differentiation Neurons Patients Pattern Peripheral Population Process Public Health Research Role Route Sensory Signal Pathway Signal Transduction Spinal Spinal Cord Spinal Ganglia Synapses Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Ventral Roots axon growth axon guidance axonal guidance base body position cell motility cell type experimental study in vitro Assay in vivo innovation migration motor neuron development mouse model myelination neural circuit neurodevelopment neuron development novel prevent prospective receptor relating to nervous system repaired segregation spinal nerve posterior root transcription factor

项目摘要

PROJECT SUMMARY: Motor neurons are the only neuronal cell type with cell bodies located within the central nervous system (CNS) and axons that project out into the periphery. Once outside of the CNS, motor axons bundle, but do not intermingle, with sensory axons as they co-extend towards peripheral targets. To establish this distinct projection pattern, motor neurons rely on combinations of molecular signaling pathways that direct them during different stages of their development. The mechanisms that constrain motor neuron cell bodies within the spinal cord while allowing motor axons to exit into the periphery are still not completely understood. I have found that a cell adhesion molecule, Transient Axonal Glycoprotein type-1 (TAG-1), is a fundamental, multifunctional regulator of motor neuron development and circuit formation. Multiple neural cell types transiently express TAG-1 during development, and while TAG-1 is expressed on motor neuron cell bodies and axons during early stages of differentiation and axon outgrowth, the function of TAG-1 in motor neurons is not known. An examination of TAG- 1 knockout mice revealed three major defects in motor neurons: (1) motor axon bundles (ventral roots) are expanded, (2) motor neuron cell bodies aberrantly leave the spinal cord, and (3) motor axons have severe guidance defects and invade dorsal root ganglia. Utilizing a combination of novel mouse genetics, whole embryo imaging, and in vitro assays, I will investigate the molecular mechanisms of TAG-1 function in motor circuit formation. I will also determine whether TAG-1 is required cell autonomously to regulate motor neuron migration, axonal growth and guidance. This proposal will elucidate the function of TAG-1 in motor neurons and uncover the fundamental mechanisms that regulate early motor neuron development. Overall, understanding the mechanisms that regulate neural circuit formation can inform future therapeutic interventions for re- establishing proper neural circuits after physical injury, neurodegeneration, or developmental mis-wiring.

项目概要：运动神经元是唯一一种细胞体位于中枢神经系统 (CNS) 内的神经元细胞类型和突出到外围的轴突。一旦离开中枢神经系统，运动轴突就会捆绑，但不会当它们共同延伸到外围目标时与感觉轴突混合。为了建立这种独特的投影模式下，运动神经元依赖于分子信号通路的组合来指导它们在不同的过程中他们的发展阶段。限制脊髓内运动神经元细胞体的机制而允许运动轴突退出到外围的情况尚未完全了解。我发现有一个细胞粘附分子瞬时轴突糖蛋白 1 型 (TAG-1) 是一种基本的多功能调节因子运动神经元发育和电路形成。多种神经细胞类型在期间短暂表达 TAG-1 TAG-1 在发育的早期阶段在运动神经元细胞体和轴突上表达分化和轴突生长，TAG-1 在运动神经元中的功能尚不清楚。 TAG 的检查- 1 基因敲除小鼠揭示了运动神经元的三大缺陷：（1）运动轴突束（腹根）扩大，（2）运动神经元细胞体异常离开脊髓，（3）运动轴突严重引导缺陷并侵入背根神经节。利用新型小鼠遗传学、整个胚胎的组合成像和体外测定，我将研究 TAG-1 在运动回路中功能的分子机制形成。我还将确定TAG-1是否是细胞自主调节运动神经元所必需的迁移、轴突生长和引导。该提案将阐明 TAG-1 在运动神经元中的功能和揭示调节早期运动神经元发育的基本机制。总体来说，理解调节神经回路形成的机制可以为未来的治疗干预提供信息在身体损伤、神经退行性疾病或发育错误后建立适当的神经回路。