MOLECULAR MECHANISMS MEDIATING NERVE-MUSCLE INTERACTIONS

描述(摘自申请者的摘要)：神经-肌肉的相互作用 在改变生长和生长所需的基因表达方面发挥重要作用 肌肉的分化。特别是，骨骼的感觉神经支配 肌肉在肌梭、机械感觉的发生中起着关键作用 脊椎动物骨骼肌中提供肢体位置的器官 (本体感觉)信息传递给中枢神经系统。肌梭是 由感觉轴突和运动轴突共同支配，但它们的发生是诱导的 特别是通过感官传入。感觉传入的趋向性效应是 对肌管亚群的转化形成肌管具有指导意义 主轴结构复杂。该复合体涉及的分子机制 人们对过程知之甚少。然而，我们最近发现， 锌指转录因子Egr3与纺锤体密切相关 形态发生，因为它在形成纺锤体中高水平表达。 发育时间点，与它们的诱导期重合，因为 Egr3基因缺陷的小鼠缺乏肌梭。Egr3似乎是一种必需的 信号转导分子在与之接触的肌管中表达 感觉轴突形成纺锤体。 我们已经概述了一个研究Egr3在中介中的功能的研究计划 肌梭形态发生的信号转导机制。 利用各种体内和体外分子技术，我们将检查 Egr3在肌管纺锤体基因表达调控中的作用 形态发生。肌梭的运动和感觉神经支配依赖于 纺锤体产生的神经营养因子NT-3和GDNF。我们会 研究Egr3是否调节这些神经营养因子，并在 Egr3基因缺陷小鼠的感觉和运动神经元缺陷。最后， 利用“功能增益”模型在体内和体外过表达Egr3， 我们将尝试识别受Egr3调控的靶基因，并开始定义 纺锤体形态发生过程中基因表达的重组。 该模型系统用于研究神经-肌肉相互作用的一个方面 有关肌梭的起源可能适用于其他 机械感官器官。人们很好地认识到，其他的起源 机械感觉器官，如太平洋小体(振动感觉)、高尔基体 肌腱器官(肌肉张力)和默克尔细胞(轻触)也被诱导 通过它们各自的感官传入神经。更透彻地了解 感觉神经元和感觉神经元之间的双向营养相互作用 机械感觉器官可能会更好地了解心力衰竭的病因。 各种感觉神经元病。

DESCRIPTION (From the Applicant's Abstract): Nerve-muscle interactions play an important role in altering gene expression required for growth and differentiation of muscles. In particular, sensory innervation of skeletal muscle plays a critical role in the genesis of muscle spindles, mechanosensory organs within vertebrate skeletal muscle that provide limb position (proprioceptive) information to the central nervous system. Muscle spindles are innervated by both sensory and motor axons but their genesis is induced specifically by sensory afferents. The tropic effects of sensory afferents are instructive for the transformation of a subpopulation of myotubes to form the complex spindle structure. The molecular mechanisms involved in this complex process are poorly understood. However, we have recently discovered that the zinc-finger transcription factor Egr3 is critically involved in spindle morphogenesis since it is expressed at high levels within forming spindles at a developmental time point that coincides with their induction and since Egr3-deficient mice lack muscle spindles. Egr3 appears to serve as an essential signal transduction molecule expressed in myotubes that have been contacted by sensory axons to form spindles. We have outlined a research program to study the function of Egr3 in mediating the signal transduction mechanisms involved in muscle spindle morphogenesis. Using a variety of in vivo and in vitro molecular techniques we will examine the role of Egr3 in orchestrating gene expression in myotubes during spindle morphogenesis. Motor and sensory innervation to muscle spindles depends upon the neurotrophic factors NT-3 and GDNF which are produced by spindles. We will investigate whether Egr3 regulates these neurotrophins and plays a role in the sensory and motor neuron defects observed in Egr3-deficient mice. Finally, using "gain-of-function" models to overexpress Egr3 both in vivo and in vitro, we will attempt to identify target genes regulated by Egr3 and begin to define the reorganization of gene expression that occurs during spindle morphogenesis. This model system for studying one aspect of nerve-muscle interaction as it relates to the genesis of muscle spindles may be applicable to other mechanosensory organs. It is well appreciated that the genesis of other mechanosensory organs such as Pacinian corpuscles (vibratory sensation), Golgi tendon organs (muscle tension) and Merkel cells (light touch) are also induced by their respective sensory afferent innervation. A more thorough understanding of the reciprocal tropic-trophic interactions between sensory neurons and mechanosensory organs may provide greater insight into the etiopathogenesis of a variety of sensory neuronopathies.