ROLE OF NEUREGULIN IN NEUROMUSCULAR SYNAPSE FORMATION

神经调节蛋白在神经肌肉突触形成中的作用

• 批准号: 6055209
• 负责人: XIA YANG
• 金额: $ 3.14万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6055209
• 关键词: animal breeding; cholinergic receptors; developmental neurobiology; gene expression; heregulin; immunocytochemistry; laboratory mouse; neuromuscular junction; neuromuscular transmission; neurotrophic factors; synaptogenesis

The formation of neuromuscular synapses requires a series of inductive interactions between presynaptic motor nerve terminals and postsynaptic muscle fibers, resulting in the formation of highly specialized pre- and post-synaptic membranes. One aspect of postsynaptic differentiation is the up-regulation of muscle acetylcholine receptor (AChR) expression selectively in synaptic nuclei of myofibers. Neuregulin (NRG), a potential signal for regulating such synapse-specific transcription, and its receptors are localized to neuromuscular synapses. NRG is synthesized both by motor neurons and muscle cells and activates AChR gene expression in cultured muscle cells. Because NRG is synthesized both by motor neurons and muscle cells and activates AChR gene expression in cultured muscle cells. Because NRG is also expressed in endocardial tissues and is required for heart development, mutant mice lacking NRG expression die at embryonic day 10, prior to neuromuscular synapse formation, due to heart malformation. Therefore, the role that NRG may play in synapse formation during development in vivo cannot be evaluated in NRG null- mutant mice. This proposal is devoted to study the role NRG may have in neuromuscular synapse formation. The general approach in this study is to produce mice lacking NRG expression selective in skeletal muscle or in motor neurons, by crossing study is to produce mice lacking NRG expression selectively in skeletal muscle or in motor neurons, by crossing NRG/flox/flox mice with NRG+/-; MLCcre or NRG+/-; HB9cre mice. The formation of neuromuscular synapses will be analyzed by immunohistochemical procedures that will allow me to assess both presynaptic and postsynaptic differentiation. This study will provide information on the function of NRG signaling in neuromuscular synapse formation and may provide insight into signaling mechanisms at interneuronal synapses in the brain.

神经肌肉突触的形成需要突触前运动神经末梢和突触后肌纤维之间的一系列诱导相互作用，从而形成高度专业化的突触前膜和突触后膜。 突触后分化的一方面是肌纤维突触核中肌肉乙酰胆碱受体（AChR）表达的选择性上调。神经调节蛋白（NRG）是调节这种突触特异性转录的潜在信号，其受体定位于神经肌肉突触。 NRG 由运动神经元和肌肉细胞合成，并激活培养的肌肉细胞中的 AChR 基因表达。因为 NRG 由运动神经元和肌肉细胞合成，并激活培养的肌肉细胞中的 AChR 基因表达。由于 NRG 也在心内膜组织中表达并且是心脏发育所必需的，因此缺乏 NRG 表达的突变小鼠在胚胎第 10 天（神经肌肉突触形成之前）因心脏畸形而死亡。因此，NRG 在体内发育过程中在突触形成中可能发挥的作用无法在 NRG 无效突变小鼠中进行评估。该提案致力于研究 NRG 在神经肌肉突触形成中的作用。本研究的一般方法是通过杂交产生骨骼肌或运动神经元选择性缺乏NRG表达的小鼠，通过杂交研究是通过NRG/flox/flox小鼠与NRG+/-杂交产生骨骼肌或运动神经元选择性缺乏NRG表达的小鼠； MLCcre 或 NRG+/-； HB9cre 小鼠。 将通过免疫组织化学程序分析神经肌肉突触的形成，这将使我能够评估突触前和突触后分化。这项研究将提供有关 NRG 信号在神经肌肉突触形成中的功能的信息，并可能深入了解大脑间神经元突触的信号机制。