Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration.
Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration.
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DOI：
10.1523/jneurosci.2269-10.2010
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发表时间：
2010-08-11
期刊：
影响因子：
--
通讯作者：
Zheng B
中科院分区：
文献类型：
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作者：
Lee JK;Chow R;Xie F;Chow SY;Tolentino KE;Zheng B
在中枢神经系统损伤后，来自髓鞘和损伤部位疤痕组织的轴突生长抑制剂被认为是轴突再生的主要障碍。几种抑制剂的存在，每一类中有多个成员，表明生长抑制的功能冗余。为了测试髓磷脂抑制途径的冗余性，我们分析了缺乏两种主要髓磷脂抑制剂Nogo和MAG及其共同受体NgR1（或NgR）的小鼠的肾上腺5-羟色胺能（5-HT）轴突再生。在完全性脊髓横断损伤后，Nogo/MAG/NgR1三突变体或NgR1单突变体均未发现损伤部位外5-HT轴突再生的显著增强。偶尔，基因型无关的5-HT轴突通过gap阳性的损伤部位的组织桥，这意味着gap阴性的病变区域对5-HT轴突具有特别的抑制作用。为了评估由gfap阴性的脑膜成纤维细胞在损伤部位表达的3类信号蛋白的作用，我们分析了缺乏3类信号蛋白的两个关键受体PlexinA3和PlexinA4的小鼠，并伴有或不伴有额外的NgR1缺失。通过完全横断损伤，PlexinA3/PlexinA4双突变体或PlexinA3/PlexinA4/NgR1三突变体未检测到5-HT或皮质脊髓轴突的再生增强。与之前的报道相反，这些数据表明，减弱髓磷脂或semaphorin介导的轴突生长抑制不足以促进5-HT轴突再生，并进一步表明，即使减弱这两类抑制影响也不足以通过完全性脊髓横断损伤促进受损轴突再生。
Following CNS injuries, axon growth inhibitors from the myelin and the scar tissue at the injury site are considered major impediments to axon regeneration. The presence of several classes of inhibitors with multiple members in each class suggests functional redundancy in growth inhibition. To test redundancy within the myelin inhibitory pathway, we analyzed raphespinal serotonergic (5-HT) axon regeneration in mice deficient in two major myelin inhibitors, Nogo and MAG, and their common receptor NgR1 (or NgR). Following a complete transection spinal cord injury, there was no significant enhancement of 5-HT axon regeneration beyond the injury site in either Nogo/MAG/NgR1 triple mutants or NgR1 single mutants. Occasional, genotype-independent traversal of 5-HT axons through GFAP-positive tissue bridges at the injury site implicates GFAP-negative lesion areas as especially inhibitory to 5-HT axons. To assess the contribution of class 3 Semaphorins that are expressed by GFAP-negative meningeal fibroblasts at the injury site, we analyzed mice deficient in PlexinA3 and PlexinA4, two key receptors for class 3 Semaphorins, with or without additional NgR1 deletion. No enhanced regeneration of 5-HT or corticospinal axons was detected in PlexinA3/PlexinA4 double mutants or PlexinA3/PlexinA4/NgR1 triple mutants through a complete transection injury. In contrast with previous reports, these data demonstrate that attenuating myelin or Semaphorin-mediated inhibition of axon growth is insufficient to promote 5-HT axon regeneration and further indicate that even attenuating both classes of inhibitory influences is insufficient to promote regeneration of injured axons through a complete transection spinal cord injury.