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题名	Wnt 信号通路在神经肌肉接头处乙酰胆碱受体聚集中的作用
作者	王佳
学位类别	博士
答辩日期	2008-12-10
授予单位	中国科学院上海生命科学研究院
授予地点	上海生命科学研究院
导师	罗振革
关键词	神经肌肉接头 突触后分化 Wnt3A β-catenin Rapsyn P65
其他题名	Role of Wnt/β-catenin Signaling in Acetylcholine Receptor
学位专业	神经生物学
中文摘要	正、负向信号间的相互作用对于神经肌肉接头处突触后结构的塑造十分重要，本文报道了Wnt3A可以通过抑制乙酰胆碱受体偶联蛋白Rapsyn的表达，进而抑制乙酰胆碱受体聚集。用Wnt3A处理培养的肌管细胞或者在肌管细胞中过量表达-catenin都可以使聚集素Agrin诱导出的乙酰胆碱受体聚集体明显减少，更重要的是，Wnt3A还可以促进乙酰胆碱受体聚集体的消散，而Wnt经典通路的拮抗剂DKK1可以阻止这种作用。有趣的是，在探索Wnt3A调节乙酰胆碱受体聚集的机制时，我们发现Wnt3A能够降低Rapsyn的蛋白表达量，Wnt3A处理或者-catenin过量表达均可以抑制培养的肌肉细胞中Rapsyn启动子的活性，这可能是通过Wnt3A/-catenin抑制了转录因子P65的转录活性来实现的。强制表达启动子不受Wnt3A调节的Rapsyn会阻止Wnt3A对于乙酰胆碱受体聚集体的消散作用，这表明Wnt3A确实是通过下调Rapsyn的表达来消散乙酰胆碱受体聚集体的，这种消散作用在体内也得到了证实，在成年小鼠腿部肌肉中电转Wnt3A 或者-catenin后同样观察到突触后结构出现异常。综上所述，这些结果显示Wnt/-catenin 信号通路在脊椎动物神经肌肉接头处突触后分化过程中，能够调节突触后蛋白Rapsyn的表达，抑制突触的形成，发挥负向调节的作用。
英文摘要	The dynamic interaction between positive and negative signals is necessary for remodeling of postsynaptic structures at the neuromuscular junction (NMJ). 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 over- expression of β-catenin, the condition mimicking the activation of 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 β-catenin over-expression, which probably inhibits the action of transcription factor P65. 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/β-catenin signaling in dispersing AChR clusters was also investigated in vivo by electroporation of Wnt3A or β-catenin into mouse limb muscles, where ectopic Wnt3A or β-catenin caused disassembly of postsynaptic apparatus. Together, these results suggest that Wnt/β-catenin signaling plays a negative role for postsynaptic differentiation at the NMJ, probably by regulating the expression of synaptic proteins, such as Rapsyn.
语种	中文
公开日期	2013-01-05
页码	105
内容类型	学位论文
源URL	[http://ir.sibs.ac.cn/handle/331001/2358]
专题	上海神经科学研究所_神经所(总)
推荐引用方式 GB/T 7714	王佳. Wnt 信号通路在神经肌肉接头处乙酰胆碱受体聚集中的作用[D]. 上海生命科学研究院. 中国科学院上海生命科学研究院. 2008.

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