Neuregulin-2 and the formation of neuromuscular synapses

描述（由申请人提供）：在哺乳动物神经肌肉接头处 (NMJ)乙酰胆碱受体（AChRs）在大脑皮层上密集聚集， 神经末梢下的肌纤维质膜。最近的研究 提供了对分子的敏锐洞察力，例如蛋白聚集蛋白， 通过神经诱导发育中的NMJ处的AChR簇。第二 神经源性信号也有助于AChRS的高浓度， 突触通过选择性激活AChR亚单位基因的转录， 这些肌肉核位于神经末梢下面。虽然 这种激活剂的分子性质仍然未知，神经调节蛋白的蛋白质 (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，它们的代码是 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，它们的结构与 NRG-1提出了它们可以解释某些活动的可能性 目前被认为是NRG-1。在NMJ，NRG-1被认为是局部激活 突触下肌核中的AChR转录。然而，我们的初步数据显示， 表明NRG-2，像NRG-1一样，在体内集中在NMJ， 诱导培养肌纤维AChR表达。这里提出的实验 旨在解决三个主要问题：（1）NRG-2的AChR诱导 活性由nrg-2基因的选择性剪接控制？(2)有哪些 NRG-2亚型由NMJ的细胞组分制成？(3)做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，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 预计将产生新的见解的分子机制，控制 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

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.