MOLECULAR MECHANISMS MEDIATING NERVE MUSCLE INTERACTIONS

描述（由申请人提供）：对介导感觉轴突-机械感受器相互作用的发育、神经支配和稳定性的分子机制知之甚少，但它们可能在与机械感受器去神经支配和轴突损失相关的人类神经病中很重要。一些人类感觉神经病主要影响大直径的感觉轴突，其优先支配肌肉和肌腱机械感受器（肌梭拉伸感受器和高尔基腱器官）以向中枢神经系统提供骨骼和肌肉位置感觉（本体感受）。在产前骨骼肌发育过程中，感觉轴突调节接触肌管中特定基因的表达，以介导牵张受体形态发生并稳定其神经支配。占主导地位的特定分子信号是未知的，但识别它们是相当大的兴趣，因为本体感觉缺陷是许多感觉神经病的常见和衰弱的方面。如果没有更好地了解参与建立和维持肌梭牵张受体神经支配的分子因素，就很难制定合理的治疗方法来减缓或逆转本体感受轴突的损失。参与由大直径轴突（la-传入神经）接触的肌管的信号转导途径和参与维持对它们的感觉和运动神经支配的分子信号知之甚少; la-传入神经提供指导性信号，其可能通过参与对纺锤体形态发生特异性的基因调控网络将肌管亚群转化为纺锤体拉伸受体。在以前的工作中，我们确定Egr 3作为纺锤体发育的一个重要的转录调节因子，其在肌管中由la-传入神经支配诱导。该研究计划概述了三个具体目标：（i）表征新的Egr 3调节的靶基因在牵张受体形态发生和神经支配中的功能，（ii）检查Egr 3介导的基因表达是否足以在不存在la-传入形态发生信号传导的情况下将肌管转化为梭内肌纤维，以及以确定Egr 3是否是将肌管命运指定为梭内肌纤维谱系所必需的。我们预计，这些研究将提供更多的了解感觉神经支配如何控制肌肉拉伸受体形态发生，并将更好地定义Egr 3在调节拉伸受体特异性基因，可能参与稳定感觉和运动神经支配的作用。肌肉和皮肤的热感受器和机械感受器的形态发生都依赖于感觉神经支配，这表明我们对神经-肌肉牵张感受器相互作用的研究可能揭示了一些共同的分子机制。

DESCRIPTION (provided by applicant): The molecular mechanisms mediating the development, innervation and stability of sensory axon- mechanoreceptor interactions are very poorly understood, yet they are likely to be important in human neuropathies associated with mechanoreceptor denervation and axon loss. Some human sensory neuropathies primarily affect large diameter sensory axons which preferentially innervate muscle and tendon mechanoreceptors (muscle spindle stretch receptors and Golgi tendon organs) to provide skeletal and muscle position sensation (proprioception) to the central nervous system. During prenatal skeletal muscle development, sensory axons regulate the expression of a specific repertoire of genes in contacted myotubes to mediate stretch receptor morphogenesis and stabilize their innervation. The specific molecular signals that predominate are unknown but identifying them is of considerable interest since proprioception deficits are a common and debilitating aspect of many sensory neuropathies. Without a better understanding of the molecular factors involved in establishing and maintaining innervation to muscle spindle stretch receptors, it will be difficult to formulate rational therapies to slow or reverse proprioceptive axon loss. The signal transduction pathways engaged in myotubes that are contacted by large diameter axons (la- afferents) and the molecular signals involved in maintaining sensory and motor innervation to them are very poorly understood; la-afferents provide instructive signals that transform a subpopulation of myotubes into spindle stretch receptors presumably by engaging gene regulatory networks that are specific for spindle morphogenesis. In previous work, we identified Egr3 as an essential transcriptional regulator of spindle development which is induced in myotubes by la-afferent innervation. This research plan is outlined in three specific aims: (i) to characterize the function of novel Egr3 regulated target genes in stretch receptor morphogenesis and innervation, (ii) to examine whether Egr3 mediated gene expression is sufficient to transform myotubes into intrafusal muscle fibers in the absence of la-afferent morphogenetic signaling and i) to determine whether Egr3 is necessary to fate specify myotubes to an intrafusal muscle fiber lineage. We anticipate that these studies will provide greater understanding of how sensory innervation controls muscle stretch receptor morphogenesis and will better define the role of Egr3 in regulating stretch receptor specific genes that may be involved in stabilizing sensory and motor innervation to them. Muscle and cutaneous thermo- and mechanoreceptors all depend upon sensory innervation for their morphogenesis suggesting that some common molecular mechanisms may be revealed by our studies focusing on nerve- muscle stretch receptor interactions.