[Molecular mechanism and regulation of axon growth inhibition].
[Molecular mechanism and regulation of axon growth inhibition].
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轴突生长抑制的分子机制及调控[J].
DOI：
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发表时间：
2007
期刊：
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通讯作者：
T. Yamashita
中科院分区：
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作者：
T. Yamashita
在成年哺乳动物中枢神经系统（CNS）中，损伤的轴突表现出非常有限的再生能力是众所周知的。由于缺乏适当的轴突再生，对成人大脑和脊髓的创伤性损伤经常导致永久性神经元缺陷，如瘫痪。已经在髓磷脂中鉴定了CNS中的几种轴突生长抑制剂，包括髓磷脂相关糖蛋白、Nogo和寡致密细胞髓磷脂糖蛋白。由Nogo受体、p75受体和LINGO-1组成的受体复合物在体外转导来自所有这些抑制剂的信号。在这些抑制剂的下游，小GTdR RhoA及其效应物Rho激酶的激活已被证明是这些抑制剂引起的神经突生长抑制和生长锥塌陷的关键因素。与这些体外研究结果一致，体内抑制RhoA或Rho激酶促进脊髓损伤后轴突生长和功能恢复。最近，几种发育指导蛋白，包括排斥性指导分子、信号蛋白和肝配蛋白被认为参与了中枢神经系统损伤后轴突生长的抑制。因此，多轴突生长抑制剂似乎有助于损伤的轴突不能再生，并且阻断多轴突生长抑制剂的治疗策略可以提供在CNS损伤后产生功能性再生的有效工具。此外，值得注意的是，突触可塑性在预先存在的途径和形成新的电路通过侧支发芽的损伤和未损伤的纤维的自发恢复过程的重要组成部分。这种现象的分子机制知之甚少，阐明这一点将有助于增强功能恢复后，不完全损伤的中枢神经系统。我将总结最近关于这些问题的调查结果。
In the adult mammalian central nervous system (CNS), it is well known that injured axons exhibit very limited regeneration ability. Due to this lack of appropriate axonal regeneration, a traumatic damage to the adult brain and spinal cord frequently causes permanent neuronal deficits such as paralysis. Several axon growth inhibitors, including myelin-associated glycoprotein, Nogo, and oligodensrocyte myelin glycoprotein, in the CNS have been identified in the myelin. Receptor complex comprising of the Nogo receptor, the p75 receptor, and LINGO-1 transduces the signals from all of these inhibitors in vitro. Downstream of these inhibitors, activation of small GTPase RhoA and its effector Rho-kinase has been shown to be a key element for neurite growth inhibition and growth cone collapse elicited by these inhibitors. Consistent with these findings in vitro, inhibition of RhoA or Rho-kinase in vivo promotes axon growth and functional recovery after spinal cord injury. Recently, several developmental guidance proteins, including repulsive guidance molecules, semaphorin, and ephrin are suggested to be involved in axon growth inhibition after injury to the CNS. Thus, multiple axon growth inhibitors seem to contribute to inability of the injured axons to regenerate, and therapeutic strategy to block the multiple axon growth inhibitors may provide efficient tools that produce functional regeneration following injuries to the CNS. In addition, it is noted that synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibers are important components of the spontaneous recovery process. The molecular mechanism of this phenomenon is poorly understood, and elucidation of this will contribute to enhancement of functional recovery after incomplete injury to the CNS. I will summarize recent findings regarding these issues.