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Neuroligin 2 Is Required for Synapse Development and Function at the Drosophila Neuromuscular Junction

alfredo 添加于 2011-1-30 23:08 | 2181 次阅读 | 0 个评论

作者
Sun M, Xing G, Yuan L, Gan G, Knight D, With SI, He C, Han J, Zeng X, Fang M, Boulianne GL, Xie W
摘要
1The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing 210009, China, 2Departments of Medical Genetics and Developmental Biology and 3Biochemistry and Molecular Biology, Medical School of Southeast University, Nanjing 210009, China, and 4Program in Developmental and Stem Cell Biology, The Hospital for Sick Children and Department Molecular Genetics, University of Toronto, Toronto, Ontario, Canada, M5G 1L7 Correspondence should be addressed to either of the following: Gabrielle L. Boulianne or Wei Xie, Toronto Medical Discovery Tower, 12th Floor, East Tower, 101 College Street, Toronto, Ontario, Canada M5G 1L7, Email: gboul@sickkids.ca; Wei Xie, The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China, E-mail: Email: wei.xie@seu.edu.cn Neuroligins belong to a highly conserved family of cell adhesion molecules that have been implicated in synapse formation and function. However, the precise in vivo roles of Neuroligins remain unclear. In the present study, we have analyzed the function of Drosophila neuroligin 2 (dnl2) in synaptic development and function. We show that dnl2 is strongly expressed in the embryonic and larval CNS and at the larval neuromuscular junction (NMJ). dnl2 null mutants are viable but display numerous structural defects at the NMJ, including reduced axonal branching and fewer synaptic boutons. dnl2 mutants also show an increase in the number of active zones per bouton but a decrease in the thickness of the subsynaptic reticulum and length of postsynaptic densities. dnl2 mutants also exhibit a decrease in the total glutamate receptor density and a shift in the subunit composition of glutamate receptors in favor of GluRIIA complexes. In addition to the observed defects in synaptic morphology, we also find that dnl2 mutants show increased transmitter release and altered kinetics of stimulus-evoked transmitter release. Importantly, the defects in presynaptic structure, receptor density, and synaptic transmission can be rescued by postsynaptic expression of dnl2. Finally, we show that dnl2 colocalizes and binds to Drosophila neurexin (dnrx) in vivo. However, whereas homozygous mutants for either dnl2 or dnrx are viable, double mutants are lethal and display more severe defects in synaptic morphology. Altogether, our data show that, although dnl2 is not absolutely required for synaptogenesis, it is required postsynaptically for synapse maturation and function.
详细资料
- 文献种类:期刊
- 期刊名称: Journal of Neuroscience
- 期刊缩写: Journal of Neuroscience
- 期卷页: 2011年第31卷第2期 687-699页
- ISBN: 0270-6474
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中加科学家发现孤独症致病基因参与突触发育

为孤独症发生的分子神经生物学机制提供重要线索

作为目前世界上患病人数增长最快的疾病之一，孤独症越来越受关注，但其发病机理依旧是一个谜团，存有争议。日前，美国《神经科学杂志》（The Journal of Neuroscience）发表了东南大学生命科学研究院谢维研究组和加拿大多伦多大学鲍利安·加布里埃尔课题组合作的研究成果，可能为孤独症发生的分子神经生物学机制提供重要线索。

大脑通过数万亿个突触连接而成的巨大通讯网络来处理信息、行使功能。突触通过自身的可塑性，传递、转变和完善信号。突触细胞粘附因子，通过连接突触前、后细胞，调节突触传递信号，并且通过形成特异性的突触功能来决定神经网络的特性。其中，非对称突触细胞粘附分子Neuroligin和Neurexin可能参与突触信号传递并与人类认知相关而最引人注目。

该项研究采用果蝇作为模式生物对Neuroligin功能进行研究，发现果蝇 Neuroligin2在胚胎和幼虫的中枢神经系统以及幼虫的神经肌肉接头部位存在较强表达，提示其可能在高级神经活动中发挥作用。研究人员进而制备突变体并用神经肌肉接头（NMJ）为研究材料探讨Neuroligin2的作用，发现了突变体果蝇运动行为缺陷和突触传递异常；深入分析显示神经肌肉接头生长缺陷，每个突触活性位点出现分化异常，突触后功能性受体的平衡遭到破坏；Neuroligin2和Neurexin双突变导致更严重的表型。这些结果表明 Neuroligin2和Neurexin参与突触的发育和突触功能的发挥。

孤独症主要特征表现为社会交往障碍、语言交流技巧障碍，以及重复刻板的行为和狭窄的兴趣。该研究工作阐明了孤独症重要的致病基因Neuroligin和Neurexin参与突触的发育与功能，为进一步探讨孤独症发病的分子机制提供了重要线索，并可能为筛选相应的药物提供较简单的模式系统。

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Neuroligin 2 Is Required for Synapse Development and Function at the Drosophila Neuromuscular Junction

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