Sensory innervation-dependent transcriptional regulation in muscle

描述(由申请人提供)：拟议的研究解决了肌肉的感觉神经元神经支配如何调节肌梭发育过程中的基因表达。肌梭是嵌入肌肉中的感觉感受器，可以检测肌肉长度的变化。每个纺锤由特殊的肌肉纤维组成，称为梭内肌纤维，以及来自感觉神经元的轴突末端，这些轴突支配这些肌肉纤维，并将长度信息传递到中枢神经系统。肌梭的形成是由肌肉纤维之间的诱导相互作用调节的，这些肌肉纤维最终将成为梭内纤维和接触它们的感觉轴突。这一诱导过程的关键部分是神经调节蛋白(NRG)1，这是一种分泌的信号蛋白，由感觉轴突释放，进而激活其受体ErbB蛋白，在接触的肌肉细胞中。建议的研究集中在ERBBS激活的细胞内途径，这是肌梭形成的关键，但在大多数情况下还没有确定。尽管细胞内的反应如何发生还不确定，但已经确定的一个关键成分是转录因子Egr3，它作为NRG-ErbB信号的一部分在转录水平上被诱导，进而激活与肌梭形成有关的各种靶基因。建议的研究集中在Egr3上游的信号传递上，通过识别诱导NRG1反应Egr3转录所需的转录调节蛋白，并确定NRG1-ErbB途径如何作用于这些转录调节蛋白。除了提供对肌梭形成的洞察，这项研究的结果也可能适用于NRG1-ErbB信号如何在其他类型的细胞中调节其功能的基因表达，作为各种信号通路的一部分的Egr3如何在这些通路中调节，以及由支配它们的感觉轴突诱导的其他机械感觉结构的形成。由于某些感觉神经疾病涉及神经及其连接的破坏，了解控制机械感觉结构形成的信号相互作用可能会建议采用再生方法来治疗某些感觉神经疾病。 与公共健康相关：这项拟议的研究解决了肌肉的感觉神经元神经支配如何调节肌梭发育过程中的基因表达，并可能适用于由支配它们的感觉轴突诱导的其他机械感觉结构的形成。某些感觉神经病涉及神经及其连接的破坏。了解控制肌梭和其他机械感觉结构形成的信号相互作用可能会提出治疗某些感觉神经疾病的再生方法。

DESCRIPTION (provided by applicant): The proposed research addresses how sensory neuron innervation of muscle regulates gene expression during muscle spindle development. Muscle spindles are sensory receptors embedded within muscle that detect changes in muscle length. Each spindle is composed of specialized muscle fibers, known as intrafusal muscle fibers, and the endings of axons from sensory neurons that innervate these muscle fibers and that convey length information to the CNS. Formation of muscle spindles is regulated by inductive interactions between muscle fibers that ultimately will become intrafusal fibers and sensory axons that contact them. A critical part of this inductive process is neuregulin (NRG) 1, a secreted signaling protein, being released by sensory axons, and in turn activating its receptors, ErbB proteins, in muscle cells that are contacted. The proposed research focuses on the intracellular pathway activated by ErbBs, which is critical for muscle spindle formation but for the most part has not been determined. Despite the uncertainty about how the intracellular response occurs, one critical component that has been identified is the transcription factor Egr3, which is transcriptionally induced as part of NRG-ErbB signaling and in turn activates various target genes involved in formation of muscle spindles. The proposed research focuses on the signaling relay that acts upstream of Egr3 by identifying transcriptional regulatory proteins that are required for inducing transcription of Egr3 in response to NRG1 and determining how these transcriptional regulatory proteins are acted upon by the NRG1-ErbB pathway. In addition to providing insight into muscle spindle formation, results obtained from this research might also be applicable to how NRG1- ErbB signaling regulates gene expression in other cell types in which it functions, to how Egr3, which functions as part of a variety of signaling pathways, is regulated within these pathways, and to formation of other mechanosensory structures that are induced by the sensory axons that innervate them. Because certain sensory neuropathies involve destruction of nerves and their connections, understanding the signaling interactions that control formation of mechanosensory structures might suggest regenerative approaches for treating certain sensory neuropathies. PUBLIC HEALTH RELEVANCE: The proposed research addresses how sensory neuron innervation of muscle regulates gene expression during muscle spindle development and may also be applicable to formation of other mechanosensory structures that are induced by the sensory axons that innervate them. Certain sensory neuropathies involve destruction of nerves and their connections. Understanding the signaling interactions that control formation of muscle spindles and other mechanosensory structures might suggest regenerative approaches for treating certain sensory neuropathies.