Wnt-Ryk Signaling Mediates Axon Growth Inhibition and Limits Functional Recovery after Spinal Cord Injury
Wnt-Ryk Signaling Mediates Axon Growth Inhibition and Limits Functional Recovery after Spinal Cord Injury
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DOI：
10.1089/neu.2008.0776
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发表时间：
2009-07-01
影响因子：
4.2
通讯作者：
Yamashita, Toshihide
中科院分区：
文献类型：
--
作者：
Miyashita, Tomohiro;Koda, Masao;Yamashita, Toshihide
Wnt蛋白是一个扩散因子大家族，在胚胎发育中发挥重要作用，包括轴模式、细胞命运指定、增殖和轴突发育。最近的研究表明，Ryk（受体相关的酪氨酸激酶）是一个保守的高亲和力的Wnt受体，Ryk-Wnt相互作用的指导皮质脊髓轴突在脊髓发育过程中。在这里，我们报告说，Ryk-Wnt信号介导的抑制皮质脊髓轴突生长在成年脊髓。在脊髓损伤后损伤部位周围的反应性星形胶质细胞中诱导Wnt-5a的表达。在体外，Wnt-5a通过激活RhoA/Rho激酶抑制出生后小脑神经元的轴突生长。在胸脊髓挫伤大鼠中，鞘内注射Ryk中和抗体导致皮质脊髓束的显著轴突生长和增强功能恢复。因此，在成年组织中重新表达的胚胎排斥线索有助于在中枢神经系统轴突再生的失败。
Wnt proteins are a large family of diffusible factors that play important roles in embryonic development, including axis patterning, cell fate specification, proliferation, and axon development. It was recently demonstrated that Ryk (receptor related to tyrosine kinase) is a conserved high-affinity Wnt receptor, and that Ryk-Wnt interactions guide corticospinal axons down the spinal cord during development. Here, we report that the Ryk-Wnt signal mediates the inhibition of corticospinal axon growth in the adult spinal cord. The expression of Wnt-5a is induced in reactive astrocytes around the injury site following a spinal cord injury. In vitro, Wnt-5a inhibits the neurite growth of postnatal cerebellar neurons by activating RhoA/Rho-kinase. In rats with thoracic spinal cord contusion, intrathecal administration of a neutralizing antibody to Ryk resulted in significant axonal growth of the corticospinal tract and enhanced functional recovery. Thus, reexpression of the embryonic repulsive cues in adult tissues contributes to the failure of axon regeneration in the central nervous system.