Understanding the Multifunctionality of TAG-1 in Motor Neuron Development

项目总结： 运动神经元是胞体位于中枢神经系统内的唯一神经细胞类型。 以及投射到外围的轴突。一旦离开中枢神经系统，运动轴突束束，但不 与感觉神经轴突混杂在一起，共同向周围目标延伸。为了建立这种独特的预测 模式，运动神经元依赖于分子信号通路的组合，在不同的 他们发展的不同阶段。限制脊髓内运动神经元胞体的机制 虽然允许运动神经轴突出口进入外周，但仍不完全清楚。我发现了一个细胞 黏附分子，瞬时轴突糖蛋白-1(Tag-1)，是一种基本的、多功能的调节因子。 运动神经元发育和回路形成。多种神经细胞类型在体内瞬时表达TAG-1 TAG-1在运动神经元胞体和轴突中表达。 TAG-1在运动神经元中的功能尚不清楚。关于标签的审查-- 1基因敲除小鼠发现运动神经元有三个主要缺陷：(1)运动轴突束(腹根) 扩张，(2)运动神经元胞体畸形离开脊髓，(3)运动轴突重 引导缺陷，侵犯背根神经节。利用一种新的小鼠遗传学组合，整个胚胎 成像和体外检测，我将研究TAG-1在马达电路中作用的分子机制 队形。我还将确定TAG-1是否是自主调节运动神经元所需的细胞 迁移、轴突生长和引导。这一建议将阐明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。总体而言，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、神经退化或发育性错误连接后建立适当的神经回路。

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.