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）：该项目的目的是阐明神经抑制蛋白（NRG-1）通过ERBB受体酪氨酸激酶（ERBB2，ERBBB3和ERBB4）的异二聚体或同型二聚体作用的机制，调节神经肌表达在Neuromuscularcular consions（NMJ）。几条证据表明，NRG-1信号通路在Schwann细胞发育和ACHR基因表达中起重要作用。 NMJ由精确排列的神经末端，雪旺氏细胞和肌肉细胞组成。 NMJ的主要特征是存在含有高浓度的乙酰胆碱受体（ACHR）的突触后设备（ACHR）与许多细胞外，跨膜和细胞质支架和信号成分密切相关。胚胎肌肉中的ACHR复合物被组织为由四个不同的亚基组成的五聚体，α，beta，伽马和三角洲，在Stoichiementry alpha2，Beta，Beta，Gamma，Delta中。 ACHR的组成从Alpha2，Beta，Gamma，Delta（胚胎形式）到Alpha2，Beta，Beta，Epsilon，Delta（成人形式）。从伽马到epsilon亚基的转换发生在前两个几周。胚胎和成人ACHR亚基基因表达的调节已成为了解突触特异性基因表达的极好模型。在本提案中，我们将通过在发育或出生后产生缺乏不同ERBB受体异二聚体或同型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。目的是： 目的1。确定神经调节蛋白信号通路在胚胎发育过程中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 目的3。确定蛋白质磷酸化/去磷酸化在神经调节的ACHR基因表达中阐明神经肌肉突触形成的机制的作用，将进一步进一步理解我们对掌管突触形成的一般原理的理解，因此，以及神经系统发展和功能的基础。这些结果无疑将为治疗神经肌肉疾病和脊髓损伤的设计策略提供关键信息。