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Wnt/ -Catenin Signaling Suppresses Rapsyn Expression and Inhibits Acetylcholine Receptor Clustering at the Neuromuscular Junction

Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2008; 283(31):21668-75. DOI: 10.1074/jbc.M709939200
Source: PubMed

ABSTRACT The dynamic interaction between positive and negative signals is necessary for remodeling of postsynaptic structures at the neuromuscular junction. Here we report that Wnt3a negatively regulates acetylcholine receptor (AChR) clustering by repressing the expression of Rapsyn, an AChR-associated protein essential for AChR clustering. In cultured myotubes, treatment with Wnt3a or overexpression of beta-catenin, the condition mimicking the activation of the Wnt canonical pathway, inhibited Agrin-induced formation of AChR clusters. Moreover, Wnt3a treatment promoted dispersion of AChR clusters, and this effect was prevented by DKK1, an antagonist of the Wnt canonical pathway. Next, we investigated possible mechanisms underlying Wnt3a regulation of AChR clustering in cultured muscle cells. Interestingly, we found that Wnt3a treatment caused a decrease in the protein level of Rapsyn. In addition, Rapsyn promoter activity in cultured muscle cells was inhibited by the treatment with Wnt3a or beta-catenin overexpression. Forced expression of Rapsyn driven by a promoter that is not responsive to Wnt3a prevented the dispersing effect of Wnt3a on AChR clusters, suggesting that Wnt3a indeed acts to disperse AChR clusters by down-regulating the expression of Rapsyn. The role of Wnt/beta-catenin signaling in dispersing AChR clusters was also investigated in vivo by electroporation of Wnt3a or beta-catenin into mouse limb muscles, where ectopic Wnt3a or beta-catenin caused disassembly of postsynaptic apparatus. Together, these results suggest that Wnt/beta-catenin signaling plays a negative role for postsynaptic differentiation at the neuromuscular junction, probably by regulating the expression of synaptic proteins, such as Rapsyn.

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    • "Moreover, b-catenin stabilization in the diaphragm results in a wider distribution of AChR clusters (Liu et al., 2012), as observed in the Dvl1 or Agrin mutant mice (Gautam et al., 1996; Henriquez et al., 2008). In contrast, b-catenin null muscles possess larger AChRs clusters and increased Rapsyn levels (Li et al., 2008; Wang et al., 2008). Together these results demonstrate that canonical Wnt signaling is a negative regulator of NMJ development and suggest that a proper balance between canonical and noncanonical Wnt signaling might modulate the size of the NMJ. "
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    • "Instead, aggregation is induced through activation of Rac1 (Henriquez et al., 2008). However, Wnt3a inhibits agrin-induced AChR clusters through the activation of the Wnt/β-catenin pathway, suggesting that Wnt signaling dynamically regulates the interaction between postsynaptic components during the establishment of neuromuscular junctions (Wang et al., 2008). Different Wnts have shown modulatory effects on glutamatergic neurotransmission. "
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    • "Instead, aggregation is induced through activation of Rac1 (Henriquez et al., 2008). However, Wnt3a inhibits Agrin-induced AChR clusters through the activation of the Wnt/␤-catenin pathway, suggesting that Wnt signaling dynamically regulates the interaction between postsynaptic components during the establishment of neuromuscular junctions (Wang et al., 2008). Besides its role in presynaptic functions, Wnt7a has also been shown to regulate the postsynaptic compartment stimulating the morphogenesis and function of excitatory dendritic spines, without affecting the inhibitory connections in the hippocampus (Ciani et al., 2011). "
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