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（由申请人提供）：在哺乳动物神经肌肉连接处 （NMJ）乙酰胆碱受体（ACHR）积聚在密集的聚集体上 肌肉纤维的质膜在神经末端下方。最近的研究 对使用的分子（例如蛋白质agrin）提供敏锐的见解 通过在发育中的NMJ上诱导ACHR簇的神经。第二 神经衍生的信号也有助于高浓度的ACHR 通过选择性激活AChR亚基基因的转录来突触 那些位于神经末端下方的肌肉核。虽然 该激活剂的分子性质仍然未知，神经结合蛋白的蛋白质 （NRG）生长因子家族是该信号的主要候选者。 有四个NRG基因：NRG-1。 NRG-2，NRG-3和NRG-4，哪个代码 具有高氨基酸同源性的蛋白质。虽然， NRG-2，NRG-3和NRG-4目前尚不清楚，它们与 NRG-1提高了他们可以考虑一些活动的可能性 目前归因于NRG-1。在NMJ，NRG-1被认为可以局部激活 突触肌核中的ACHR转录。但是，我们的初步数据 建议NRG-2像NRG-1一样集中在体内的NMJ上，可以 在培养的肌肉纤维中诱导ACHR表达。这里提出的实验 旨在解决三个主要问题：（1）是NRG-2的ACHR诱导 通过NRG-2基因的替代剪接控制的活性？ （2）什么是 NRG-2由NMJ的细胞成分制成的同工型？ （3）做NRG-2和 NRG-1在NMJ上执行冗余功能？检验的假设是 运动神经元制造的特定NRG-2同工型参与激活 NMJ的ACHR表达，NRG-2和NRG-1调节重叠，但 不同的突触后基因。拟议研究的结果是 预计将对控制的分子机制产生新的见解 NMJ处的神经递质受体密度，可能在这种对照处 大脑中的突触。