Section of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Neurosci Lett. 2011 Nov 14;505(2):165-70. doi: 10.1016/j.neulet.2011.10.012. Epub 2011 Oct 12.
The axons of the adult mammalian brain and spinal cord fail to regenerate after injury, and it has been suggested that Nogo-66 could prevent CNS axon repair. However, the mechanism of Nogo-66 inhibiting neurite outgrowth remains unknown. Our previous results indicated that protein kinase B (PKB) is involved in the inhibition of the neurite outgrowth by Nogo-66. Glycogen synthase kinase-3β (GSK-3β) is implicated in many processes in the nervous system, including differentiation, specification, polarity, plasticity and axon growth. In addition, GSK-3β is one of the most important molecules downstream of PKB. In the present study, we report on the role of GSK-3β signaling on Nogo-66-treated mouse neuroblastoma N2a cells. Nogo-66 reduced the phosphorylation of GSK-3β at Ser9 in N2a cells. In contrast, pretreatment with SB216763, a specific inhibitor of GSK-3β, resulted in an amelioration of neurite outgrowth by Nogo-66, compared with the Nogo-66 alone group (P<0.05). Moreover, we performed RNA interference experiments to knock down GSK-3β expression levels in N2a cells via transient transfection of shRNA plasmids. The inhibition of neurite outgrowth by Nogo-66 was subdued in shRNA cells, compared to the non-RNAi cells (P<0.05). Taken together, these data suggest that GSK-3β is involved in the inhibition by Nogo-66 of neurite outgrowth in N2a cells.
成年哺乳动物大脑和脊髓的轴突在受伤后无法再生，有人提出 Nogo-66 可以阻止中枢神经系统轴突修复。然而，Nogo-66 抑制神经突生长的机制尚不清楚。我们之前的结果表明，蛋白激酶 B（PKB）参与了 Nogo-66 抑制神经突生长的过程。糖原合成酶激酶-3β（GSK-3β）参与神经系统的许多过程，包括分化、特化、极性、可塑性和轴突生长。此外，GSK-3β 是 PKB 下游最重要的分子之一。在本研究中，我们报告了 GSK-3β 信号通路在 Nogo-66 处理的小鼠神经母细胞瘤 N2a 细胞中的作用。Nogo-66 降低了 N2a 细胞中 GSK-3β 丝氨酸 9 位的磷酸化。相比之下，用 GSK-3β 的特异性抑制剂 SB216763 预处理，与 Nogo-66 单独处理组相比（P<0.05），Nogo-66 处理的神经突生长得到改善。此外，我们通过瞬时转染 shRNA 质粒，在 N2a 细胞中进行 RNA 干扰实验以敲低 GSK-3β 的表达水平。与非 RNAi 细胞相比，Nogo-66 对神经突生长的抑制作用在 shRNA 细胞中减弱（P<0.05）。总之，这些数据表明 GSK-3β 参与了 Nogo-66 抑制 N2a 细胞神经突生长的过程。
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