Isaacman-Beck Jesse, Schneider Valerie, Franzini-Armstrong Clara, Granato Michael
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6058, USA.
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6058, USA.
Neuron. 2015 Nov 18;88(4):691-703. doi: 10.1016/j.neuron.2015.10.004. Epub 2015 Nov 5.
Functional PNS regeneration requires injured axons to return to their original synaptic targets, yet the mechanisms underlying target-selective regeneration have remained elusive. Using live-cell imaging in zebrafish we find that regenerating motor axons exhibit a strong preference for their original muscle territory and that axons probe both correct and incorrect trajectories extensively before selecting their original path. We show that this process requires the glycosyltransferase lh3 and that post-injury expression of lh3 in Schwann cells is sufficient to restore target-selective regeneration. Moreover, we demonstrate that Schwann cells neighboring the transection site express the lh3 substrate collagen4a5 and that during regeneration collagen4a5 destabilizes axons probing inappropriate trajectories to ensure target-selective regeneration, possibly through the axonal repellant slit1a. Our results demonstrate that selective ECM components match subpopulations of regenerating axons with their original targets and reveal a previously unappreciated mechanism that conveys synaptic target selection to regenerating axons in vivo. VIDEO ABSTRACT.
功能性外周神经系统（PNS）的再生需要受损轴突回到其原来的突触靶点，然而靶点选择性再生背后的机制仍然难以捉摸。通过在斑马鱼中进行活细胞成像，我们发现再生的运动轴突对其原来的肌肉区域表现出强烈的偏好，并且轴突在选择其原来的路径之前会广泛探测正确和错误的轨迹。我们表明，这个过程需要糖基转移酶lh3，并且施万细胞中lh3在损伤后的表达足以恢复靶点选择性再生。此外，我们证明横断部位附近的施万细胞表达lh3底物胶原蛋白4a5，并且在再生过程中，胶原蛋白4a5会使探测不适当轨迹的轴突不稳定，以确保靶点选择性再生，可能是通过轴突排斥分子slit1a。我们的结果表明，选择性细胞外基质（ECM）成分将再生轴突亚群与其原来的靶点相匹配，并揭示了一种以前未被认识到的机制，该机制在体内将突触靶点选择传递给再生轴突。视频摘要。
