Neuregulin-2 and the formation of neuromuscular synapses

Neuregulin-2 与神经肌肉突触的形成

• 批准号: 6620674
• 负责人: MENDELL RIMER
• 金额: $ 20.39万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620674
• 关键词: Schwann cells; binding sites; biological signal transduction; cell membrane; electron microscopy; genetic transcription; immunocytochemistry; in situ hybridization; laboratory mouse; microarray technology; motor neurons; muscle cells; nerve growth factors; neuregulins; neuromuscular junction; neurotransmitter receptor; polymerase chain reaction; protein isoforms; protein protein interaction; protein structure function; receptor expression; synapses; synaptogenesis; tissue /cell culture

DESCRIPTION (provided by applicant): At the mammalian neuromuscular junction (NMJ) acetylcholine receptors (AChRs) accumulate in dense aggregates on the muscle fiber's plasma membrane beneath the nerve terminal. Recent studies provide keen insights into molecules, such as the protein agrin, that are used by the nerve to induce AChR clusters at the developing NMJ. A second nerve-derived signal also contributes to the high concentration of AChRS at the synapse by selectively activating transcription of the AChR subunit genes in those muscle nuclei positioned underneath the nerve terminal. Although the molecular nature of this activator remains unknown, proteins of the neuregulin (NRG) family of growth factors are the leading candidates for this signal. There are four NRG genes: nrg-1. nrg-2, nrg-3, and nrg-4, which code for proteins with high amino acid homology. Although, the biological functions of NRG-2, NRG-3, and NRG-4 are currently unknown, their structural similarity with NRG-1 raises the possibility that they could account for some of the activities presently attributed to NRG-1. At the NMJ, NRG-1 is thought to locally activate AChR transcription in subsynaptic myonuclei. However, our preliminary data suggest that NRG-2, like NRG-1, is concentrated at the NMJ in vivo and can induce AChR expression in cultured muscle fibers. The experiments proposed here are aimed at addressing three major questions: (1) Is NRG-2's AChR-inducing activity controlled by alternative splicing of the nrg-2 gene? (2) What are the NRG-2 isoforms made by the cellular components of the NMJ? (3) Do NRG-2 and NRG-1 perform redundant functions at the NMJ? The hypothesis being tested is that specific NRG-2 isoforms made by motor neurons are involved in activating AChR expression at the NMJ, and that NRG-2 and NRG-1 regulate overlapping but different sets of postsynaptic genes. Results from the proposed research are expected to yield new insights into the molecular mechanisms that control neurotransmitter receptor density at the NMJ, which may bear on such control at synapses in the brain.

描述(申请人提供)：在哺乳动物神经肌肉交界处 (NMJ)乙酰胆碱受体(AChRs)聚集在 神经末梢下的肌肉纤维质膜。最新研究 提供对分子的敏锐洞察力，例如蛋白质集聚蛋白 通过神经在发育中的NMJ诱导AChR簇。一秒钟 神经来源的信号也是导致AChRS在大脑中的高浓度的原因 选择性激活AChR亚单位基因转录的突触 那些位于神经末梢下方的肌肉核。尽管 这种激活剂的分子性质尚不清楚，即神经调节蛋白的蛋白质 (NRG)一系列增长因素是这一信号的主要候选者。 有四个NRG基因：NRG-1。NRG-2、NRG-3和NRG-4，它们的编码 氨基酸同源性高的蛋白质。虽然，它的生物学功能 NRG-2、NRG-3和NRG-4目前未知，它们的结构相似性与 NRG-1提出了他们可能解释其中一些活动的可能性 目前归因于NRG-1。在NMJ，NRG-1被认为是局部激活的 Achr在突触下肌核的转录。然而，我们的初步数据 提示NRG-2和NRG-1一样，在体内集中在NMJ，并且可以 诱导培养的肌纤维中AChR的表达。这里提出的实验 旨在解决三个主要问题：(1)NRG-2的S是否具有AChR诱导作用 由NRG-2基因选择性剪接控制的活性？(2)什么是 由NMJ细胞成分制造的NRG-2亚型？(3)NRG-2和 NRG-1在NMJ执行冗余功能？正在测试的假设是 运动神经元产生的特定NRG-2亚型参与激活 Achr在NMJ的表达，以及NRG-2和NRG-1调节重叠，但 不同的突触后基因。建议的研究结果如下 有望对控制人类健康的分子机制产生新的见解 NMJ的神经递质受体密度，这可能与这种控制有关 大脑中的突触。