Biglycan is an extracellular MuSK binding protein important for synapse stability.
Biglycan is an extracellular MuSK binding protein important for synapse stability.
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DOI：
10.1523/jneurosci.4610-11.2012
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发表时间：
2012-02-15
期刊：
影响因子：
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通讯作者：
Fallon JR
中科院分区：
文献类型：
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作者：
Amenta AR;Creely HE;Mercado ML;Hagiwara H;McKechnie BA;Lechner BE;Rossi SG;Wang Q;Owens RT;Marrero E;Mei L;Hoch W;Young MF;McQuillan DJ;Rotundo RL;Fallon JR
受体酪氨酸激酶MuSK对于神经-肌肉突触的形成和维持是必不可少的。MuSK对终板区原基的预形成和作为聚集蛋白介导的突触后分化的信号受体是必需的。MuSK相关蛋白如Dok 7、LRP 4和Wnt 11 r参与神经肌肉接头形成的这些早期事件。然而，调节突触稳定性的机制知之甚少。在这里，我们研究了一个新的作用，细胞外基质蛋白双糖链在突触的稳定性。胎儿和出生后早期双糖链蛋白聚糖缺失（bgn-/o）肌肉的突触发育与野生型对照没有区别。然而，出生后5周的神经肌肉突触在bgn-/o小鼠是异常的，判断存在的交界处的褶皱，增加分割和焦点错位的乙酰胆碱酯酶和AChRs。这些观察结果表明，以前占据的突触前和突触后区域已经被腾空。双糖蛋白聚糖结合MuSK，并且该受体酪氨酸激酶的水平在bgn-/o突触处选择性降低。在bgn-/o肌管中，聚集蛋白诱导的MuSK磷酸化和AChR聚集的初始阶段是正常的，但AChR簇是不稳定的。这种稳定性缺陷可以通过加入纯化的双糖链蛋白聚糖而基本上得到挽救。总之，这些结果表明双糖链蛋白聚糖是MuSK的细胞外配体，其对于突触稳定性是重要的。
The receptor tyrosine kinase MuSK is indispensable for nerve-muscle synapse formation and maintenance. MuSK is necessary for pre-patterning of the endplate zone anlage and as a signaling receptor for agrin-mediated postsynaptic differentiation. MuSK-associated proteins such as Dok7, LRP4, and Wnt11r are involved in these early events in neuromuscular junction formation. However, the mechanisms regulating synapse stability are poorly understood. Here we examine a novel role for the extracellular matrix protein biglycan in synapse stability. Synaptic development in fetal and early postnatal biglycan null (bgn-/o) muscle is indistinguishable from wild type controls. However, by 5 wks after birth nerve-muscle synapses in bgn-/o mice are abnormal as judged by the presence of perijunctional folds, increased segmentation and focal misalignment of acetylcholinesterase and AChRs. These observations indicate that previously occupied pre- and post- synaptic territory has been vacated. Biglycan binds MuSK and the levels of this receptor tyrosine kinase are selectively reduced at bgn-/o synapses. In bgn-/o myotubes, the initial stages of agrin-induced MuSK phosphorylation and AChR clustering are normal, but the AChR clusters are unstable. This stability defect can be substantially rescued by the addition of purified biglycan. Together, these results indicate that biglycan is an extracellular ligand for MuSK that is important for synapse stability.