Sensory innervation-dependent transcriptional regulation in muscle

描述（由申请人提供）：拟议的研究涉及肌肉感觉神经元的神经支配如何调节肌肉纺锤体发育过程中的基因表达。肌纺锤体是嵌入肌肉中的感觉受体，可以检测肌肉长度的变化。每个纺锤体是由特殊的肌纤维组成的，称为肠内肌纤维，以及支配这些肌纤维并向中枢神经系统传递长度信息的感觉神经元的轴突末梢。肌纺锤体的形成是由肌纤维之间的感应相互作用调节的，这些肌纤维最终将成为流内纤维和与它们接触的感觉轴突。这个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，并反过来激活其受体，即接触的肌肉细胞中的ErbB蛋白。本研究的重点是由erbb激活的细胞内通路，该通路对肌肉纺锤体的形成至关重要，但大部分尚未确定。尽管细胞内反应如何发生尚不确定，但已确定的一个关键成分是转录因子Egr3，它作为NRG-ErbB信号传导的一部分被转录诱导，进而激活参与肌纺锤体形成的各种靶基因。本研究拟重点研究作用于Egr3上游的信号转导，鉴定诱导Egr3响应NRG1转录所需的转录调节蛋白，并确定NRG1- erbb通路如何作用于这些转录调节蛋白。除了提供对肌纺锤体形成的见解外，本研究的结果也可能适用于NRG1- ErbB信号如何调节其功能的其他细胞类型中的基因表达，以及作为各种信号通路一部分的Egr3如何在这些通路中被调节，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为治疗某些感觉神经病提供再生方法。

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.