MOLECULAR MECHANISMS MEDIATING NERVE-MUSCLE INTERACTIONS

描述（来自申请人的摘要）：神经-肌肉相互作用发挥作用 在改变生长所需的基因表达中的重要作用， 肌肉的分化。特别是骨骼肌的感觉神经支配 肌肉在肌梭的发生、机械感觉、 脊椎动物骨骼肌内提供肢体位置的器官 （本体感受）信息传递到中枢神经系统。肌梭是 由感觉和运动轴突支配，但它们的发生是诱导的 特别是通过感觉传入。感觉传入神经的向性作用是 这对于肌管亚群的转化以形成肌细胞具有指导意义。 复杂的纺锤体结构该复合物涉及的分子机制 过程知之甚少。然而，我们最近发现， 锌指转录因子Egr 3在纺锤体形成中起重要作用 形态发生，因为它在形成纺锤体的过程中以高水平表达， 发育时间点与其诱导时间一致， egr 3缺陷小鼠缺乏肌梭。Egr 3似乎是一种重要的 信号转导分子在肌管中表达， 感觉轴突形成纺锤体 我们已经概述了一个研究计划，以研究Egr 3在介导 肌梭形态发生的信号转导机制。 使用各种体内和体外分子技术，我们将研究 Egr 3在肌管纺锤体基因表达调控中作用 形态发生肌梭的运动和感觉神经支配取决于 由纺锤体产生的神经营养因子NT-3和GDNF。我们将 研究Egr 3是否调节这些神经营养因子，并在神经营养因子中发挥作用。 在Egr 3缺陷小鼠中观察到感觉和运动神经元缺陷。最后， 使用“功能获得”模型在体内和体外过表达Egr 3， 我们将尝试鉴定Egr 3调控的靶基因，并开始定义 在纺锤体形态发生过程中发生的基因表达重组。 该模型系统用于研究神经-肌肉相互作用的一个方面， 与肌梭的发生有关的可能适用于其他 机械感觉器官很好地理解，其他的起源 机械感觉器官，如Pacinian小体（振动感觉），高尔基体 腱器官（肌肉张力）和默克尔细胞（轻触）也被诱导 通过它们各自的感觉传入神经支配。更透彻的理解 感觉神经元之间的相互热带营养相互作用， 机械感觉器官可以提供更深入的了解发病机制， 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.