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Title: Dishevdled和MuSK以及PAKI的相互作用调节乙酰胆碱受体的聚集
Author: 王强
Degree Level: 博士
Issued Date: 2002
Degree Grantor: 中国科学院上海生命科学院神经科学研究所
Place of Degree Grantor: 中国科学院上海生命科学院神经科学研究所
Supervisor: 梅林
Keyword: MuSK受体酪氨酸激酶 ; 突触 ; 神经肌肉接头
Alternative Title: Regulation of AChR Clustering by Dishevelled Interacting with MuSK and PAK1
Abstract: 神经递质受体在突触后膜高度聚集是突触结构重要特征。功能上,高度聚集的受体保证了高效而准确的突触传递。因此,对神经递质受体聚集的分子机制的研究是神经发育生物学中的重要课题。神经肌肉接头是研究突触发育的重要模型,其突触后膜上聚集着大量的烟碱型乙酞胆碱受体。研究证明运动神经元合成并释放Agrin,激活肌肉细胞膜上的如SK,引起乙酞胆碱受体的聚集。人们对有关MuSK下游的信号传递途径所知甚少。通过研究肌肉细胞内与MtlSK相互作用的蛋白,本文探讨了在神经肌肉接头突触形成过程中介导乙酞胆碱受体聚集的一个可能信号传递途径。我们用酵母双杂交技术发现Dvl可以和MuSK的胞浆区结合。Dvl是Wnt 信号传递途径中的重要分子。它在发育过程中的表达分布和MoSK相似,富集于神经肌肉接头。我们证明这两个蛋白有直接的相互作用,而且内源性的Dvl和MuSK可以相互结合。抑市叮Dvl蛋白的表达或者阻断内源性的Dvl和MuSK间的结合会抑制Agrin引起的肌肉细胞表面乙酚胆碱受体聚集,以及神经肌肉接头突触后膜乙酰胆碱受体聚集,同时突触自发电位的幅度也因此明显下降。进一步的研究发现,在与MusK结合的同时,Dvl可以同细胞内的丝氨酸/苏氨酸激酶PAKI相互作用,形成一个三分子复合体。Agr in会增加肌肉细胞中PAKI的激酶活性。抑制PAK1激酶的活性会抑制Agrin引起的乙酰胆碱受体聚集。本文揭示了Dvl和PAKI在Agrin/MuSK引起乙酞胆碱受体聚集的信号传递途径中的作用,提示Dvl这个Wnt信号传递途径中的关键分子可能参与调节突触形成的过程。
English Abstract: Synapses are characterized by highly concentrated neurotransmitter receptors in the postsynaptic membrane. The formation of neuromuscular junction (NMJ) and the clustering of nAChR (nicotinic acetylcholine receptor) at NMJ had been studied extensively. Although it is already known that MuSK acts as an essential component of agrin receptor complex and is required for nAChR clustering at the NMJ, the underlying molecular mechanisms remain unclear. In present study, we devoted our effort to identifying possible signaling pathway involving in AChR clustering by studying MuSK interacting proteins in muscle cells.We report here that using MuSK intracellular domain as bait, we pulled out Dishevelled (Dvl), a signaling molecule important for cell polarity, as MuSK interacting protein in yeast two hybrid assay. MuSK interacts with Dvl in muscle cells directly and specifically. The tempo and spatial expression profiles of MuSK and Dvl are similar in muscle. Disruption of the MuSK-Dvl interaction inhibits Agrin-induced and neuron-induced AChR clustering. Expression of dominant negative Dvll in the postsynaptic muscle cells reduces the amplitude of spontaneous synaptic currents at the NMJ.Moreover, Dvll interacts with a downstream kinase P21~activated-kinasel (PAK1), MuSK, Dvl and PAK1 form complex among them. Agrin activates PAK1, and the activation of PAK1 by agrin requires Dvl. Inhibition of PAK1 activity attenuates AChR clustering.These results demonstrate the important roles of Dvl and PAK in Agrin/MuSK induced AChR clustering, and reveal a novel function of Dvl in synapse development.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2261
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
Dishevdled和MuSK以及PAKI的相互作用调节乙酰胆碱受体的聚集.王强[d].中国科学院上海生命科学院神经科学研究所,2002.20-25
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