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首页> 外文期刊>Nature >C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains
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C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains

机译：秀丽隐杆线虫突触后域的胆碱能与GABA能

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摘要

Because most neurons receive thousands of synaptic inputs, the neu-ronal membrane is a mosaic of specialized microdomains where neurotransmitter receptors cluster in register with the corresponding presynaptic neurotransmitter release sites. In many cases the coordinated differentiation of presynaptic and postsynaptic domains implicates trans-synaptic interactions between membrane-associated proteins such as neurexins and neuroligins. The Caenorhabditis elegansneuromuscular junction (NMJ) provides a genetically tractable system in which to analyse the segregation of neurotransmitter receptors, because muscle cells receive excitatory innervation from cholinergic neurons and inhibitory innervation from GABAergic neurons4. Here we show that Ce-Punctin/madd-4 (ret. 5), the C. elegans orthologue of mammalian punctin-1 and punctin-2, encodes neurally secreted isoforms that specify the excitatory or inhibitory identity of postsynaptic NMJ domains. These proteins belong to the ADAMTS (a disintegrin and met alloprotease with thrombospondin repeats)-like family, a class of extracellular matrix proteins related to the ADAM proteases but devoid of proteolytic activity. Ce-Punctin deletion causes the redistribution of synaptic acetylcholine and GAB A_A (γ-aminobutyric acid type A) receptors into extrasynaptic clusters, whereas neuronal presynaptic boutons remain unaltered. Alternative promoters generate different Ce-Punctin isoforms with distinct functions. A short isoform is expressed by cholinergic and GABAergic motoneurons and localizes to excitatory and inhibitory NMJs, whereas long isoforms are expressed exclusively by cholinergic motoneurons and are confined to cholinergic NMJs. The differential expression of these isoforms controls the congruence between presynaptic and postsynaptic domains: specific disruption of the short isoform relocalizes GABA_A receptors from GABAergic to cholinergic synapses, whereas expression of a long isoform in GABAergic neurons recruits acetylcholine receptors to GABAergic NMJs. These results identify Ce-Punctin as a previously unknown synaptic organizer and show that presynaptic and postsynaptic domain identities can be genetically uncoupled in vivo. Because human punctin-2 was identified as a candidate gene for schizophrenia, ADAMTS-like proteins may also control synapse organization in the mammalian central nervous system.
机译：由于大多数神经元接收成千上万的突触输入，因此神经元膜是特定微区的镶嵌体，其中神经递质受体聚集在相应的突触前神经递质释放部位。在许多情况下，突触前和突触后域的协调分化牵涉到膜相关蛋白（如神经毒素和神经胶蛋白）之间的反式突触相互作用。秀丽隐杆线虫神经肌肉接头（NMJ）提供了一个遗传上易处理的系统，可在其中分析神经递质受体的分离，因为肌肉细胞从胆碱能神经元获得兴奋性神经支配，而从GABA能神经元获得抑制性神经支配4。在这里，我们显示Ce-Punctin / madd-4（第5版），哺乳动物的Punctin-1和Punctin-2的秀丽隐杆线虫直向同源物，编码神经元分泌的同工型，它们指定了突触后NMJ域的兴奋性或抑制性。这些蛋白质属于ADAMTS（一种整合素，与具有血小板反应蛋白重复序列​​的异源蛋白酶相遇）样家族，是一类与ADAM蛋白酶相关的细胞外基质蛋白，但缺乏蛋白水解活性。 Ce-Punctin缺失导致突触乙酰胆碱和GAB A_A（γ-氨基丁酸A型）受体重新分布到突触外簇中，而神经元突触前钮扣保持不变。替代启动子产生具有不同功能的不同的Ce-Punctin亚型。胆碱能和GABA能运动神经元表达短的同工型，并定位于兴奋性和抑制性NMJ，而胆碱能运动神经元仅表达长同工型，并局限于胆碱能的NMJ。这些同工型的差异表达控制突触前和突触后结构域之间的一致性：短同工型的特异性破坏将GABA_A受体从GABA能性突触重新定位到胆碱能突触，而长同工型的表达在GABA能神经元中将乙酰胆碱受体募集到GABA能NMJs。这些结果确定Ce-Punctin是一个以前未知的突触组织者，并显示突触前和突触后域身份可以在体内遗传解耦。由于人类突突蛋白2被确定为精神分裂症的候选基因，ADAMTS样蛋白也可能控制哺乳动物中枢神经系统中的突触组织。

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  • 来源
    《Nature》 |2014年第7510期|466-470|共5页
  • 作者

    Berangere Pinan-Lucarre; Haijun Tu; Marie Pierron; Pablo Ibanez Cruceyra; Hong Zhan; Christian Stigloher; Janet E. Richmond; Jean-Louis Bessereau;

  • 作者单位

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France,University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534,69622 Villeurbanne, France;

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France,University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534,69622 Villeurbanne, France;

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France,University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534,69622 Villeurbanne, France;

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France;

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France,University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534,69622 Villeurbanne, France;

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France;

    Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, USA;

    Institute of Biology, Ecole Normale Superieure, 75005 Paris, France,University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534,69622 Villeurbanne, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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