Schwann Cells and Deleted in Colorectal Carcinoma Direct Regenerating Motor Axons Towards Their Original Path
Schwann Cells and Deleted in Colorectal Carcinoma Direct Regenerating Motor Axons Towards Their Original Path
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DOI：
10.1523/jneurosci.2007-14.2014
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发表时间：
2014-10-29
影响因子：
5.3
通讯作者：
Granato, Michael
中科院分区：
文献类型：
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作者：
Rosenberg, Allison F.;Isaacman-Beck, Jesse;Granato, Michael
在完全切断神经后，再生周围轴突的一个主要挑战是穿过损伤部位并导航到它们原来的轨迹。损伤部位远端失神经的雪旺细胞分泌促进轴突生长的因子，并作为轴突基质，但雪旺细胞是否也积极地将轴突引向其原始轨迹尚不清楚。利用斑马鱼的活细胞成像，我们首次可视化了神经横断后远端雪旺细胞如何作为轴突碎片改变形态，以及一旦再生生长锥体穿过损伤部位并沿着勾勒出原始神经路径的远端雪旺细胞生长，雪旺细胞形态如何逆转。在缺乏雪旺细胞的突变体中，再生的生长锥体以与野生型相当的速度延伸，但往往无法穿过损伤部位，而是沿着异常的轨迹漂移。在损伤部位提供生长允许但无雪旺细胞的支架不足以将再生的生长锥体引导到原始路径，这提供了令人信服的证据，表明失神经的雪旺细胞积极地将再生轴突引导到损伤部位的原始轨迹。为了确定在体内引导轴突再生的信号，我们检查了缺乏在结直肠癌(DCC)指导受体中缺失的突变。在这些DCC突变体中，很大一部分再生运动轴突沿着异常的轨迹延伸，类似于我们在没有雪旺细胞的突变体中观察到的情况。因此，雪旺细胞和DCC介导的引导在再生早期引导生长锥体穿过横断间隙并进入其原始轴突轨迹是至关重要的。
After complete nerve transection, a major challenge for regenerating peripheral axons is to traverse the injury site and navigate toward their original trajectory. Denervated Schwann cells distal to the lesion site secrete factors promoting axonal growth and serve as an axonal substrate, yet whether Schwann cells also actively direct axons toward their original trajectory is unclear. Using live-cell imaging in zebrafish, we visualize for the first time how in response to nerve transection distal Schwann cells change morphology as axons fragment, and how Schwann cell morphology reverses once regenerating growth cones have crossed the injury site and have grown along distal Schwann cells outlining the original nerve path. In mutants lacking Schwann cells, regenerating growth cones extend at rates comparable with wild type yet frequently fail to cross the injury site and instead stray along aberrant trajectories. Providing growth-permissive yet Schwann cell-less scaffolds across the injury site was insufficient to direct regenerating growth cones toward the original path, providing compelling evidence that denervated Schwann cells actively direct regenerating axons across the injury site toward their original trajectory. To identify signals that guide regenerating axons in vivo, we examined mutants lacking the deleted in colorectal carcinoma (DCC) guidance receptor. In these dcc mutants, a significant fraction of regenerating motor axons extended along aberrant trajectories, similar to what we observe in mutants lacking Schwann cells. Thus, Schwann cell and dcc-mediated guidance are critical early during regeneration to direct growth cones across the transection gap and onto their original axonal trajectory.