Regulation of Synaptic Gene Expression in Muscle

肌肉突触基因表达的调节

• 批准号: 7173267
• 负责人: KUO-FEN LEE
• 金额: $ 41.18万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173267
• 关键词: Acetylcholine; Adult; Agrin; Birth; Cholinergic Receptors; Chromosome Pairing; Complex; Development; Embryo; Embryonic Development; ErbB4 gene; Gene Expression; Genetic; Goals; Mediating; Modeling; Mus; Muscle; Muscle Cells; Mutant Strains Mice; Nerve; Neuregulins; Neuromuscular Diseases; Neuromuscular Junction; Phosphorylation; Physiological; Play; Protein Dephosphorylation; Receptor Protein-Tyrosine Kinases; Regulation; Role; Schwann Cells; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Spinal cord injury; Synapses; Week; base; design; extracellular; nervous system development; postnatal; postsynaptic; receptor; scaffold; stoichiometry; synaptogenesis

DESCRIPTION (provided by applicant): The goal of this project is to elucidate the mechanisms by which neuregulin (NRG-1), acting through heterodimers or homodimers of erbB receptor tyrosine kinases (erbB2, erbB3 and erbB4), regulates synaptic gene expression at neuromuscular junctions (NMJs). Several lines of evidence suggest that NRG-1 signaling pathways play an important role in Schwann cell development and AChR gene expression. NMJs are comprised of precisely aligned nerve terminals, Schwann cells and muscle cells. A cardinal feature of the NMJ is the presence of a postsynaptic apparatus containing high concentrations of acetylcholine receptors (AChRs) closely associated with numerous extracellular, transmembrane, and cytoplasmic scaffolding and signaling components. The AChR complex in embryonic muscle is organized as a pentamer comprised of four distinct subunits, alpha, beta, gamma, and delta, in the stoichiometry alpha2, beta, gamma, delta. The composition of the AChR undergoes a postnatal switch from alpha2, beta, gamma, delta (embryonic form) to alpha2, beta, epsilon, delta (adult form). The switch from gamma to epsilon subunit occurs during the first two postnatal weeks. Regulation of embryonic and adult AChR subunit gene expression has been an excellent model to understand synapse-specific gene expression. In the present proposal, we will determine the physiological role of erbB receptors in synapse-specific AChR gene expression by generating mice deficient in different erbB receptor heterodimers or homodimers during development or after birth. Furthermore, primary muscle cells will be established from these mutant mice to elucidate signal transduction pathways underlying synapse-specific AChR gene expression. The aims are: Aim 1. To determine the role of the neuregulin signaling pathway in AChR gene expression during embryonic development Aim 2. To determine the role of the neuregulin signaling pathway in regulating expression of adult AchRe subunit Aim 3. To determine the role of protein phosphorylation/dephosphorylation in neuregulin-regulated AchR gene expression Elucidating the mechanisms in the control of neuromuscular synapse formation will further our understanding of general principles governing synapse formation and, hence, the basis of nervous system development and function. These results will undoubtedly provide crucial information in designing strategies to treat neuromuscular diseases and spinal cord injury.

描述（由申请人提供）：该项目的目标是阐明神经调节蛋白（NRG-1）通过 erbB 受体酪氨酸激酶（erbB2、erbB3 和 erbB4）的异二聚体或同二聚体发挥作用，调节神经肌肉突触基因表达的机制。路口 (NMJ)。多项证据表明 NRG-1 信号通路在雪旺细胞发育和 AChR 基因表达中发挥重要作用。 NMJ 由精确排列的神经末梢、雪旺细胞和肌肉细胞组成。 NMJ 的一个主要特征是存在突触后装置，其中含有高浓度的乙酰胆碱受体 (AChR)，与许多细胞外、跨膜和细胞质支架和信号传导成分密切相关。胚胎肌肉中的 AChR 复合物被组织为五聚体，由四个不同的亚基 α、β、γ 和 δ 组成，化学计量为 α2、β、γ、δ。 AChR 的组成经历出生后从 alpha2、beta、gamma、delta（胚胎形式）到 alpha2、beta、epsilon、delta（成人形式）的转变。从 γ 亚基到 ε 亚基的转变发生在出生后的前两周。胚胎和成人 AChR 亚基基因表达的调节是了解突触特异性基因表达的绝佳模型。在本提案中，我们将通过产生在发育期间或出生后缺乏不同 erbB 受体异二聚体或同二聚体的小鼠来确定 erbB 受体在突触特异性 AChR 基因表达中的生理作用。此外，将从这些突变小鼠中建立原代肌肉细胞，以阐明突触特异性 AChR 基因表达的信号转导途径。目标是： 目的 1. 确定胚胎发育过程中神经调节蛋白信号通路在 AChR 基因表达中的作用 目的 2. 确定神经调节蛋白信号通路在调节成人 AchRe 亚基表达中的作用 目标 3. 确定蛋白质磷酸化/去磷酸化在神经调节蛋白调节的 AchR 基因表达中的作用 阐明控制神经肌肉突触形成的机制将进一步加深我们对控制突触形成的一般原理的理解，从而为神经系统发育和发育奠定基础。功能。这些结果无疑将为设计治疗神经肌肉疾病和脊髓损伤的策略提供重要信息。