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


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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    • "Wnt3a disassembles AChR clusters possibly through a β-catenin-dependent, but TCF-independent, signaling that results in the down-regulation of rapsyn (Wang et al., 2008). In addition, treatment of myotubes with lithium (Sharma and Wallace, 2003) or BIO (Henriquez et al., 2008), two GSK3β inhibitors that activate the Wnt/β-catenin pathway, inhibits agrin-induced AChR clustering. "
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    ABSTRACT: Cumulative evidence indicates that Wnt pathways play crucial and diverse roles to assemble the neuromuscular junction (NMJ), a peripheral synapse characterized by the clustering of acetylcholine receptors (AChR) on postsynaptic densities. The molecular determinants of Wnt effects at the NMJ are still to be fully elucidated. We report here that the Wnt receptor Frizzled-9 (Fzd9) is expressed in developing skeletal muscles during NMJ synaptogenesis. In cultured myotubes, gain-and loss-of-function experiments revealed that Fzd9-mediated signaling impairs the AChR-clustering activity of agrin, an organizer of postsynaptic differentiation. Overexpression of Fzd9 induced the cytosolic accumulation of β-catenin, a key regulator of Wnt signaling. Consistently, Fzd9 and β-catenin localize in the postsynaptic domain of embryonic NMJs in vivo. Our findings represent the first evidence pointing to a crucial role of a Fzd-mediated, β-catenin-dependent signaling on the assembly of the vertebrate NMJ.
    Full-text · Article · Apr 2014 · Frontiers in Cellular Neuroscience
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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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    ABSTRACT: Synapse formation requires the coordinated formation of the presynaptic terminal, containing the machinery for neurotransmitter release, and the postsynaptic side that possesses the machinery for neurotransmitter reception. For coordinated pre- and postsynaptic assembly signals across the synapse are required. Wnt secreted proteins are well-known synaptogenic factors that promote the recruitment of presynaptic components in diverse organisms. However, recent studies demonstrate that Wnts act directly onto the postsynaptic side at both central and peripheral synapses to promote postsynaptic development and synaptic strength. This review focuses on the role of Wnts in postsynaptic development at central synapses and the neuromuscular junction. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
    Full-text · Article · Nov 2013 · Developmental Neurobiology
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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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    ABSTRACT: The Wnt signaling pathway plays a role in the development of the central nervous system and growing evidence indicates that Wnts also regulates the structure and function of the adult nervous system. Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. In the nervous system, Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function, and neuronal plasticity. Wnt factors can signal through three very well characterized cascades: canonical or β-catenin pathway, planar cell polarity pathway and calcium pathway that control different processes. However, divergent downstream cascades have been identified to control neuronal morphogenesis. In the nervous system, the expression of Wnt proteins is a highly controlled process. In addition, deregulation of Wnt signaling has been associated with neurodegenerative diseases. Here, we will review different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis. Finally, the role of Wnt pathway components on Alzheimer's disease will be revised.
    Full-text · Article · Jul 2013 · Frontiers in Cellular Neuroscience
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