Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction
Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction
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DOI：
10.1242/jcs.072090
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发表时间：
2010-11-15
影响因子：
4
通讯作者：
Sonderegger, Peter
中科院分区：
文献类型：
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作者：
Bolliger, Marc F.;Zurlinden, Andreas;Sonderegger, Peter
在神经肌肉接头（NMJ）形成的初始阶段，神经源性聚集蛋白与肌肉自主机制合作，在神经肌肉接触部位组织和稳定斑块样突触后特化。随后的NMJ成熟到特征性的椒盐卷饼样外观需要广泛的结构重组。我们发现菌斑到椒盐卷饼成熟的进程是由聚集蛋白调控的。通过转基因过表达的聚集蛋白裂解蛋白酶，神经胰蛋白酶，在运动神经元过度分裂聚集蛋白导致过度重组活动的NMJ，导致突触专业化的快速分散。相反，运动神经元中抗切割聚集蛋白的表达减缓了NMJ重塑并延迟了NMJ成熟。神经胰蛋白酶是CNS中唯一的聚集蛋白裂解蛋白酶，被排除作为NMJ的生理性聚集蛋白裂解蛋白酶，因为NMJ成熟在神经胰蛋白酶缺陷小鼠中是正常的。总之，我们的分析特征聚集蛋白裂解在其蛋白水解的α和β-网站的一个尚未指定的蛋白酶作为一个监管的访问，以减轻聚集蛋白依赖的约束在NMJ成熟的终板重组。
During the initial stage of neuromuscular junction (NMJ) formation, nerve-derived agrin cooperates with muscle-autonomous mechanisms in the organization and stabilization of a plaque-like postsynaptic specialization at the site of nerve-muscle contact. Subsequent NMJ maturation to the characteristic pretzel-like appearance requires extensive structural reorganization. We found that the progress of plaque-to-pretzel maturation is regulated by agrin. Excessive cleavage of agrin via transgenic overexpression of an agrin-cleaving protease, neurotrypsin, in motoneurons resulted in excessive reorganizational activity of the NMJs, leading to rapid dispersal of the synaptic specialization. By contrast, expression of cleavage-resistant agrin in motoneurons slowed down NMJ remodeling and delayed NMJ maturation. Neurotrypsin, which is the sole agrin-cleaving protease in the CNS, was excluded as the physiological agrin-cleaving protease at the NMJ, because NMJ maturation was normal in neurotrypsin-deficient mice. Together, our analyses characterize agrin cleavage at its proteolytic alpha-and beta-sites by an as-yet-unspecified protease as a regulatory access for relieving the agrin-dependent constraint on endplate reorganization during NMJ maturation.