Manitt Colleen, Wang David, Kennedy Timothy E, Howland Dena R
Centre for Neuronal Survival, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
J Neurosci Res. 2006 Dec;84(8):1808-20. doi: 10.1002/jnr.21070.
Netrin-1 regulates axon extension during embryonic development and is expressed by neurons and myelinating oligodendrocytes in the adult CNS. To investigate the potential role of netrin-1 after spinal cord injury, we examined the expression of netrin-1 and netrin receptors after sagittal myelotomy in adult rats. This lesion targets spinal commissural projections, which respond to netrin-1 during development. Netrin-1 mRNA and protein levels were dramatically reduced at the site of injury and reduced expression persisted for at least 7 months. Neither netrin-1 protein nor mRNA was associated with the glial scar, but netrin-1 was expressed by neurons and oligodendrocytes immediately adjacent to the lesion. The post-injury distribution detected is similar to that reported for myelin-associated inhibitors of axon regeneration, such as Nogo, and is distinct from the distribution of inhibitors associated with a glial scar. DCC and UNC-5 homologue (UNC5H) expression also was reduced after injury. Although UNC5H levels recovered, DCC expression at the site of injury remained approximately 50% of pre-injury values at 7 months. Increased UNC5H immunoreactivity was associated with fibers in the superficial layers of the dorsal horn and in fibers located in white matter adjacent to the lesion. The dominant expression of UNC5H on axons and neurons in the spinal cord after injury and the persistent expression of netrin-1 by oligodendrocytes surrounding the lesion are consistent with the hypothesis that netrin-1 is a myelin-associated inhibitor of axonal regeneration after spinal cord injury.
在胚胎发育过程中，Netrin-1调节轴突延伸，且在成体中枢神经系统中由神经元和形成髓鞘的少突胶质细胞表达。为了研究脊髓损伤后Netrin-1的潜在作用，我们检测了成年大鼠矢状面脊髓切开术后Netrin-1及其受体的表达。该损伤针对脊髓连合投射，其在发育过程中对Netrin-1有反应。损伤部位的Netrin-1 mRNA和蛋白水平显著降低，且表达降低持续至少7个月。Netrin-1蛋白和mRNA均与胶质瘢痕无关，但Netrin-1在紧邻损伤处的神经元和少突胶质细胞中表达。损伤后检测到的分布与轴突再生的髓鞘相关抑制剂（如Nogo）报道的分布相似，且与胶质瘢痕相关抑制剂的分布不同。损伤后DCC和UNC-5同源物（UNC5H）的表达也降低。尽管UNC5H水平恢复，但损伤部位的DCC表达在7个月时仍约为损伤前值的50%。UNC5H免疫反应性增加与背角浅层纤维以及损伤附近白质中的纤维有关。损伤后脊髓中轴突和神经元上UNC5H的优势表达以及损伤周围少突胶质细胞中Netrin-1的持续表达与以下假设一致，即Netrin-1是脊髓损伤后轴突再生的髓鞘相关抑制剂。
