Fournier Alyson E, Takizawa Bayan T, Strittmatter Stephen M
Department of Neurology and Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Neurosci. 2003 Feb 15;23(4):1416-23. doi: 10.1523/JNEUROSCI.23-04-01416.2003.
Myelin-associated inhibitors limit axonal regeneration in the injured brain and spinal cord. A common target of many neurite outgrowth inhibitors is the Rho family of small GTPases. Activation of Rho and a downstream effector of Rho, p160ROCK, inhibits neurite outgrowth. Here, we demonstrate that Rho is directly activated by the myelin-associated inhibitor Nogo-66. Using a binding assay to measure Rho activity, we detected increased levels of GTP Rho in PC12 and dorsal root ganglion (DRG) cell lysates after Nogo-66 stimulation. Rho activity levels were not affected by Amino-Nogo stimulation. Rho inactivation with C3 transferase promotes neurite outgrowth of chick DRG neurons in vitro, but with the delivery method used here, it fails to promote neurite outgrowth after corticospinal tract (CST) lesions in the adult rat. Inhibition of p160ROCK with Y-27632 also promotes neurite outgrowth on myelin-associated inhibitors in vitro. Furthermore, Y-27632 enhances sprouting of CST fibers in vivo and accelerates locomotor recovery after CST lesions in adult rats.
髓磷脂相关抑制因子限制受损脑和脊髓中的轴突再生。许多神经突生长抑制因子的一个共同靶点是小GTP酶的Rho家族。Rho及其下游效应物p160ROCK的激活会抑制神经突生长。在此，我们证明Rho被髓磷脂相关抑制因子Nogo-66直接激活。使用结合测定法测量Rho活性，我们检测到在Nogo-66刺激后，PC12和背根神经节（DRG）细胞裂解物中GTP-Rho水平升高。Rho活性水平不受氨基-Nogo刺激的影响。用C3转移酶使Rho失活可促进鸡DRG神经元在体外的神经突生长，但采用此处使用的递送方法，它无法促进成年大鼠皮质脊髓束（CST）损伤后的神经突生长。用Y-27632抑制p160ROCK也可促进体外神经突在髓磷脂相关抑制因子上的生长。此外，Y-27632可增强成年大鼠体内CST纤维的出芽，并加速CST损伤后的运动恢复。
