Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin
Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin
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DOI：
10.1073/pnas.0806300105
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发表时间：
2008-12-02
影响因子：
11.1
通讯作者：
Salinas, Patricia C.
中科院分区：
文献类型：
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作者：
Henriquez, Juan P.;Webb, Anna;Salinas, Patricia C.
WNT蛋白通过刺激突触组装来调节中枢突触的形成，但它们在脊椎动物神经肌肉接头(NMJ)中的作用尚不清楚。WNT3在运动神经元-肌肉神经支配期间由脊髓外侧运动神经元表达。通过对雏鸡翅膀功能的获得和丧失的研究，我们证明了Wnt信号对于乙酰胆碱受体(AChR)簇的形成是必要的，而不会影响肌肉的生长。同样，Wnt信号缺失的杂乱-1突变小鼠的横隔膜在簇分布上也存在缺陷。在培养的肌管中，WNT3增加了集聚蛋白诱导的AChR簇的数量和大小，集聚蛋白是一种对NMJ发育至关重要的神经源性信号。WNT3不通过典型的Wnt途径发出信号来诱导簇形成。相反，WNT3通过激活rac1诱导不稳定的AChR微簇的快速形成，这些微簇只有在集聚蛋白存在的情况下才聚集成大簇。我们的数据揭示了WRITS通过激活rac1增强集聚蛋白功能在脊椎动物NMJ突触后组装中的作用。
Wnt proteins regulate the formation of central synapses by stimulating synaptic assembly, but their role at the vertebrate neuromuscular junction (NMJ) is unclear. Wnt3 is expressed by lateral motoneurons of the spinal cord during the period of motoneuron-muscle innervation. Using gain- and loss-of-function studies in the chick wing, we demonstrate that Wnt signaling is necessary for the formation of acetylcholine receptor (AChR) clusters without affecting muscle growth. Similarly, diaphragms from Dishevelled-1 mutant mice with deficiency in Wnt signaling exhibit defects in cluster distribution. In cultured myotubes, Wnt3 increases the number and size of AChR clusters induced by agrin, a nerve-derived signal critical for NMJ development. Wnt3 does not signal through the canonical Wnt pathway to induce cluster formation. Instead, Wnt3 induces the rapid formation of unstable AChR micro-clusters through activation of Rac1, which aggregate into large clusters only in the presence of agrin. Our data reveal a role for Writs in post-synaptic assembly at the vertebrate NMJ by enhancing agrin function through Rac1 activation.