Funakoshi H, Risling M, Carlstedt T, Lendahl U, Timmusk T, Metsis M, Yamamoto Y, Ibáñez C F
Department of Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5269-74. doi: 10.1073/pnas.95.9.5269.
Peripheral nerve injury markedly regulates expression of neurotrophins and their receptors in the lesioned nerve. However, the role of endogenously produced neurotrophins in the process of nerve regeneration is unclear. Expression of a multifunctional neurotrophin, pan-neurotrophin-1 (PNT-1), was targeted to the peripheral nerves of transgenic mice by using a gene promoter that is specifically activated after nerve lesion but that is otherwise silent in all other tissues and during development. PNT-1 is a chimeric neurotrophin that combines the active sites of the neurotrophins nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 and binds and activates all known neurotrophin receptors. In adult transgenic mice, PNT-1 was highly expressed in transected but not in intact sciatic nerve. Morphometric analyses at the electron microscopy level showed increased and accelerated recovery of axon diameter of myelinated fibers in crushed peripheral nerves of transgenic mice compared with wild type. Examination of nerve bundles in target tissues indicated accelerated reinnervation of foot pad dermis and flexor plantaris muscle in transgenic mice. Moreover, transected sensory and motor axons of transgenic mice showed faster and increased return of neurophysiological responses, suggesting an accelerated rate of axonal elongation. Importantly, transgenic mice also showed a markedly ameliorated loss of skeletal muscle weight, indicating functional regeneration of motor axons. Together, these data provide evidence, at both the anatomical and functional levels, that neurotrophins endogenously produced by the lesioned nerve are capable of significantly accelerating the regeneration of both sensory and motor axons after peripheral nerve damage. In addition, our results indicate that exogenous PNT-1 administration may be an effective therapeutic treatment of peripheral nerve injuries.
周围神经损伤显著调节受损神经中神经营养因子及其受体的表达。然而，内源性产生的神经营养因子在神经再生过程中的作用尚不清楚。通过使用一种基因启动子，将多功能神经营养因子泛神经营养因子-1（PNT-1）的表达靶向转基因小鼠的周围神经，该启动子在神经损伤后被特异性激活，但在所有其他组织以及发育过程中均保持沉默。PNT-1是一种嵌合神经营养因子，它结合了神经生长因子、脑源性神经营养因子和神经营养因子-3的活性位点，并能结合并激活所有已知的神经营养因子受体。在成年转基因小鼠中，PNT-1在横断的坐骨神经中高度表达，但在完整的坐骨神经中不表达。电子显微镜水平的形态计量分析显示，与野生型相比，转基因小鼠受损周围神经中有髓纤维的轴突直径恢复增加且加速。对靶组织中神经束的检查表明，转基因小鼠足垫真皮和足底屈肌的神经再支配加速。此外，转基因小鼠横断的感觉和运动轴突显示神经生理反应恢复更快且增强，表明轴突伸长速率加快。重要的是，转基因小鼠还显示骨骼肌重量的损失明显减轻，表明运动轴突的功能再生。总之，这些数据在解剖学和功能水平上均提供了证据，表明受损神经内源性产生的神经营养因子能够显著加速周围神经损伤后感觉和运动轴突的再生。此外，我们的结果表明，外源性给予PNT-1可能是治疗周围神经损伤的一种有效方法。
