Glypican Is a Modulator of Netrin-Mediated Axon Guidance.
Glypican Is a Modulator of Netrin-Mediated Axon Guidance.
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DOI：
10.1371/journal.pbio.1002183
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发表时间：
2015-07
期刊：
影响因子：
9.8
通讯作者：
Bénard CY
中科院分区：
文献类型：
--
作者：
Blanchette CR;Perrat PN;Thackeray A;Bénard CY
Netrin是一种关键的轴突导向因子，在神经回路形成过程中定向轴突生长。然而，netrin及其受体在细胞外环境中的调节机制在很大程度上是未知的。在这里，我们表明，在秀丽隐杆线虫，LON-2/磷脂酰肌醇蛋白聚糖，硫酸乙酰肝素蛋白聚糖，调节β-6/netrin信号，并可能通过与β-40/DCC受体的相互作用做到这一点。我们发现，在LON-2/磷脂酰肌醇蛋白聚糖不存在的情况下，发展中的轴突方向错误时，的LON-1/狭缝的指导途径受到损害，LON-2/磷脂酰肌醇蛋白聚糖功能的吸引力和排斥性的LON-6/netrin途径。我们发现，核心LON-2/磷脂酰肌醇蛋白聚糖蛋白，缺乏其硫酸乙酰肝素链，和分泌形式的LON-2/磷脂酰肌醇蛋白聚糖的轴突指导功能。我们还发现，LON-2/磷脂酰肌醇蛋白聚糖的功能，从表皮基质细胞，以指导轴突，我们提供的证据表明，LON-2/磷脂酰肌醇蛋白聚糖协会与ESTA-40/DCC受体表达细胞。我们建议，LON-2/磷脂酰肌醇蛋白聚糖作为一个调制器的<$-40/DCC介导的指导微调轴突反应的<$-6/netrin信号迁移过程中。在线虫中的工作表明，蛋白聚糖磷脂酰肌醇蛋白聚糖在神经系统发育期间充当netrin信号的细胞外调节剂，与表达netrin受体的细胞相互作用。在神经系统的发育过程中，迁移的轴突在复杂的环境中导航以到达其目标目的地。这些定向迁移对于确保神经系统的正确布线和功能至关重要，并由引导线索和受体指示。相对于大量的神经元迁移，有一组非常小的指导线索和受体，这表明这些指导线索的作用可能会通过调节机制而多样化。我们已经解决了这个问题，在遗传上易处理的线虫秀丽隐杆线虫。我们确定，迁移神经元的反应，一个关键的指导线索，β-6/netrin，是由一个特定的蛋白聚糖，LON-2/磷脂酰肌醇蛋白聚糖调制。我们表明，LON-2/磷脂酰肌醇蛋白聚糖可能通过与细胞表面的β-40/DCC netrin受体相互作用来进行这种调节。我们建议，LON-2/磷脂酰肌醇蛋白聚糖作为一个细胞外调制器的β-40/DCC介导的指导微调轴突反应的β-6/netrin信号迁移过程中。
Netrin is a key axon guidance cue that orients axon growth during neural circuit formation. However, the mechanisms regulating netrin and its receptors in the extracellular milieu are largely unknown. Here we demonstrate that in Caenorhabditis elegans, LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling and may do this through interactions with the UNC-40/DCC receptor. We show that developing axons misorient in the absence of LON-2/glypican when the SLT-1/slit guidance pathway is compromised and that LON-2/glypican functions in both the attractive and repulsive UNC-6/netrin pathways. We find that the core LON-2/glypican protein, lacking its heparan sulfate chains, and secreted forms of LON-2/glypican are functional in axon guidance. We also find that LON-2/glypican functions from the epidermal substrate cells to guide axons, and we provide evidence that LON-2/glypican associates with UNC-40/DCC receptor–expressing cells. We propose that LON-2/glypican acts as a modulator of UNC-40/DCC-mediated guidance to fine-tune axonal responses to UNC-6/netrin signals during migration. Work in nematodes shows that the proteoglycan glypican acts as an extracellular modulator of netrin signals during nervous system development, interacting with cells that express the netrin receptor. During the development of the nervous system, migrating axons are guided as they navigate through complex environments to reach their target destinations. These directed migrations are essential to ensure the proper wiring and function of the nervous system and are instructed by guidance cues and receptors. There is a remarkably small set of guidance cues and receptors relative to the large number of neuronal migrations, suggesting that the actions of these guidance cues might be diversified by regulatory mechanisms. We have addressed this question in the genetically tractable nematode Caenorhabditis elegans. We identify that the response of migrating neurons to a key guidance cue, UNC-6/netrin, is modulated by a specific proteoglycan, LON-2/glypican. We show that LON-2/glypican may carry out this regulation by interacting with the UNC-40/DCC netrin receptor on the cell surface. We propose that LON-2/glypican acts as an extracellular modulator of UNC-40/DCC-mediated guidance to fine-tune axonal responses to UNC-6/netrin signals during migration.
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