W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, 604 Allison Road, NJ 08854, USA.
Neuroscience. 2011 Jun 2;183:238-50. doi: 10.1016/j.neuroscience.2011.03.043. Epub 2011 Apr 2.
Adult zebrafish, by virtue of exhibiting spontaneous recovery after spinal lesion, have evolved into a paradigmatic vertebrate model system to identify novel genes vital for successful regeneration after spinal cord injury. Due to a remarkable level of conservation between zebrafish and human genomes, such genes, once identified, could point to possibilities for addressing the multiple issues on how to deal with functional recovery after spinal cord injury in humans. In the current study, the extracellular matrix glycoprotein tenascin-C was studied in the zebrafish spinal cord injury model to assess the often disparate functions of this multidomain molecule under in vivo conditions. This in vivo study was deemed necessary since in vitro studies had shown discrepant functional effects on neurite outgrowth: tenascin-C inhibits neurite outgrowth when presented as a molecular barrier adjacent to a conducive substrate, but enhances neurite outgrowth when presented as a uniform substrate. Thus, our current study addresses the question as to which of these features prevails in vivo: whether tenascin-C reduces or enhances axonal regrowth after injury in a well accepted vertebrate model of spinal cord injury. We show upregulation of tenascin-C expression in regenerating neurons of the nucleus of median longitudinal fascicle (NMLF) in the brainstem and spinal motoneurons. Inhibition of tenascin-C expression by antisense oligonucleotide (morpholino) resulted in impaired locomotor recovery, reduced regrowth of axons from brainstem neurons and reduced synapse formation by the regrowing brainstem axons on spinal motoneurons, all vital indicators of regeneration. Our results thus point to an advantageous role of tenascin-C in promoting spinal cord regeneration, by promoting axonal regrowth and synapse formation in the spinal cord caudal to the lesion site after injury.
成鱼斑马鱼由于在脊髓损伤后表现出自发恢复的能力，已经进化成为一种典范的脊椎动物模型系统，用于鉴定新的基因，这些基因对于脊髓损伤后的成功再生至关重要。由于斑马鱼和人类基因组之间存在显著的保守性，一旦确定了这些基因，就有可能为解决人类脊髓损伤后如何实现功能恢复的多个问题指明方向。在本研究中，研究了细胞外基质糖蛋白 tenascin-C 在斑马鱼脊髓损伤模型中的作用，以评估该多结构域分子在体内条件下的通常不同的功能。进行这项体内研究是必要的，因为体外研究显示出对神经突生长的功能作用存在差异：tenascin-C 在作为紧邻有利底物的分子屏障存在时会抑制神经突生长，但在作为均匀底物存在时会增强神经突生长。因此，我们当前的研究解决了以下问题：在公认的脊椎动物脊髓损伤模型中，tenascin-C 是减少还是增强损伤后的轴突再生：tenascin-C 在脑桥的中纵束核（NMLF）的再生神经元和脊髓运动神经元中表达上调。通过反义寡核苷酸（morpholino）抑制 tenascin-C 的表达会导致运动恢复受损、脑桥神经元的轴突再生减少以及再生的脑桥轴突在脊髓运动神经元上形成的突触减少，所有这些都是再生的重要指标。因此，我们的研究结果表明 tenascin-C 在促进脊髓再生方面具有有利作用，通过促进损伤后损伤部位以下脊髓中的轴突再生和突触形成来促进脊髓再生。
