Goldshmit Yona, Galea Mary P, Wise Graham, Bartlett Perry F, Turnley Ann M
Center for Neuroscience and School of Physiotherapy, University of Melbourne, Melbourne, Victoria 3010, Australia.
J Neurosci. 2004 Nov 10;24(45):10064-73. doi: 10.1523/JNEUROSCI.2981-04.2004.
Spinal cord injury usually results in permanent paralysis because of lack of regrowth of damaged neurons. Here we demonstrate that adult mice lacking EphA4 (-/-), a molecule essential for correct guidance of spinal cord axons during development, exhibit axonal regeneration and functional recovery after spinal cord hemisection. Anterograde and retrograde tracing showed that axons from multiple pathways, including corticospinal and rubrospinal tracts, crossed the lesion site. EphA4-/- mice recovered stride length, the ability to walk on and climb a grid, and the ability to grasp with the affected hindpaw within 1-3 months of injury. EphA4 expression was upregulated on astrocytes at the lesion site in wild-type mice, whereas astrocytic gliosis and the glial scar were greatly reduced in lesioned EphA4-/- spinal cords. EphA4-/- astrocytes failed to respond to the inflammatory cytokines, interferon-gamma or leukemia inhibitory factor, in vitro. Neurons grown on wild-type astrocytes extended shorter neurites than on EphA4-/- astrocytes, but longer neurites when the astrocyte EphA4 was blocked by monomeric EphrinA5-Fc. Thus, EphA4 regulates two important features of spinal cord injury, axonal inhibition, and astrocytic gliosis.
脊髓损伤通常会导致永久性瘫痪，因为受损神经元无法再生。在此我们证明，成年 EphA4 基因缺失小鼠（-/-），即在发育过程中对脊髓轴突正确引导必不可少的一种分子缺失的小鼠，在脊髓半切术后表现出轴突再生和功能恢复。顺行和逆行示踪显示，包括皮质脊髓束和红核脊髓束在内的多条通路的轴突穿过了损伤部位。EphA4-/- 小鼠在损伤后 1 - 3 个月内恢复了步幅、在网格上行走和攀爬的能力以及用患侧后爪抓握的能力。在野生型小鼠中，损伤部位的星形胶质细胞上 EphA4 的表达上调，而在 EphA4-/- 脊髓损伤部位，星形胶质细胞增生和胶质瘢痕大大减少。在体外，EphA4-/- 星形胶质细胞对炎性细胞因子干扰素 -γ 或白血病抑制因子无反应。在野生型星形胶质细胞上生长的神经元长出的神经突比在 EphA4-/- 星形胶质细胞上生长的神经元短，但当星形胶质细胞 EphA4 被单体 EphrinA5-Fc 阻断时，神经突更长。因此，EphA4 调节脊髓损伤的两个重要特征，即轴突抑制和星形胶质细胞增生。
