Regulation of Synaptic Extracellular Matrix Composition Is Critical for Proper Synapse Morphology
Regulation of Synaptic Extracellular Matrix Composition Is Critical for Proper Synapse Morphology
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DOI：
10.1523/jneurosci.1183-14.2014
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发表时间：
2014-09-17
影响因子：
5.3
通讯作者：
Shen, Kang
中科院分区：
文献类型：
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作者：
Kurshan, Peri T.;Phan, Allan Q.;Shen, Kang
突触被一层细胞外基质（ECM）包围，这有助于它们的发育和维持。ECM的组成是由蛋白酶动态控制的，但ECM的精确组成如何影响突触形态在很大程度上是未知的。通过无偏正向遗传筛选，我们发现秀丽隐杆线虫gon-1，一种保守的细胞外ADAMTS蛋白酶，是维持神经肌肉接头处正确突触形态所必需的。在gon-1突变体中，一旦突触形成完成，运动神经元突触前静脉曲张发育成含有突触囊泡和活性区蛋白的大球状突起。突触前轴突突起与突触后肌膜紧密贴壁。肌肉特异性肌动蛋白切割蛋白cofilin（unc-60）的突变抑制了轴突表型，表明肌肉生长是突触前突起所必需的。gon-1突变体也可以通过ECM组分胶原IV（EMB-9）和纤蛋白（FBL-1）的损失而被抑制。我们认为，GON-1调节了一个发育开关的初始“促生长”阶段，在此期间，肌肉手臂生长出来，并形成与运动神经元轴突的突触。我们假设这种转换涉及胶原IV（EMB-9）的降解或重组，而FBL-1通过稳定EMB-9对抗GON-1。我们的研究结果描述了一种调节突触ECM成分的机制，并揭示了精确的ECM成分对神经元形态和突触完整性的重要性。
Synapses are surrounded by a layer of extracellular matrix (ECM), which is instrumental for their development and maintenance. ECM composition is dynamically controlled by proteases, but how the precise composition of the ECM affects synaptic morphology is largely unknown. Through an unbiased forward genetic screen, we found that Caenorhabditis elegans gon-1, a conserved extracellular ADAMTS protease, is required for maintaining proper synaptic morphology at the neuromuscular junction. In gon-1 mutants, once synapse formation is complete, motor neuron presynaptic varicosities develop into large bulbous protrusions that contain synaptic vesicles and active zone proteins. A concomitant overgrowth of postsynaptic muscle membrane is found in close apposition to presynaptic axonal protrusions. Mutations in the muscle-specific, actin-severing protein cofilin (unc-60) suppress the axon phenotype, suggesting that muscle outgrowth is necessary for presynaptic protrusions. gon-1 mutants can also be suppressed by loss of the ECM components collagen IV (EMB-9) and fibulin (FBL-1). We propose that GON-1 regulates a developmental switch out of an initial "pro-growth" phase during which muscle arms grow out and form synapses with motor neuron axons. We postulate that this switch involves degradation or reorganization of collagen IV (EMB-9), whereas FBL-1 opposes GON-1 by stabilizing EMB-9. Our results describe a mechanism for regulating synaptic ECM composition and reveal the importance of precise ECM composition for neuronal morphology and synapse integrity.