Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury
Glial scar expression of CHL1, the close homolog of the adhesion molecule L1, limits recovery after spinal cord injury
复制标题
DOI：
10.1523/jneurosci.0739-07.2007
复制
发表时间：
2007-07-04
影响因子：
5.3
通讯作者：
Schachner, Melitta
中科院分区：
文献类型：
--
作者：
Jakovcevski, Igor;Wu, Junfang;Schachner, Melitta
Ig超家族黏附分子CHL1是黏附分子L1的紧密同系物，在体外可促进轴突生长、神经元迁移和存活。我们利用成年CHL1缺陷(CHL1(-/-))小鼠和野生型(CHL1(+/+))小鼠，测试了CHL1类似于其近缘同源基因L1的CHL1是否对脊髓损伤的恢复有有益影响。与我们的假设相反，我们发现，在胸髓受压后3-6周，CHL1(-/-)小鼠的功能恢复(通过运动评级和基于视频的运动分析评估)比野生型小鼠有所改善。更好的功能与腰椎脊髓单胺能神经再支配的增强和创伤后运动神经元周围突触重排模式的改变有关。野生型小鼠的恢复受限可能与损伤中心GFAP阳性星形胶质细胞CHL1表达的早期和持续(损伤后3-56d)上调有关。在完整的脊髓和培养的星形胶质细胞中，碱性成纤维细胞生长因子诱导CHL1和GFAP的表达增强，碱性成纤维细胞生长因子参与脊髓损伤的病理生理学。这种上调可被依赖于成纤维细胞生长因子受体的细胞外信号调节激酶、钙/钙调蛋白依赖的激酶和磷脂酰肌醇-3信号通路的抑制剂所阻断。在神经元和星形胶质细胞的同质和异质共培养中，只有当CHL1同时存在于两种细胞类型上时，才能观察到突起生长减少。这些发现和CHL1-CHL1亲性相互作用的新的体外证据表明，CHL1是一种胶质瘢痕成分，通过亲性结合机制限制创伤后轴突的生长和脊髓神经回路的重塑。
The Ig superfamily adhesion molecule CHL1, the close homolog of the adhesion molecule L1, promotes neurite outgrowth, neuronal migration, and survival in vitro. We tested whether CHL1, similar to its close homolog L1, has a beneficial impact on recovery from spinal cord injury using adult CHL1-deficient (CHL1(-/-)) mice and wild-type (CHL1(+/+)) littermates. In contrast to our hypothesis, we found that functional recovery, assessed by locomotor rating and video-based motion analyses, was improved in CHL1(-/-) mice compared with wild- type mice at 3-6 weeks after compression of the thoracic spinal cord. Better function was associated with enhanced monoaminergic reinnervation of the lumbar spinal cord and altered pattern of posttraumatic synaptic rearrangements around motoneurons. Restricted recovery of wild-type mice was likely related to early and persistent (3-56 d after lesion) upregulation of CHL1 in GFAP-positive astrocytes at the lesion core. In both the intact spinal cord and cultured astrocytes, enhanced expression of CHL1 and GFAP was induced by application of basic fibroblast growth factor, a cytokine involved in the pathophysiology of spinal cord injury. This upregulation was abolished by inhibitors of FGF receptor-dependent extracellular signal-regulated kinase, calcium/calmodulin-dependent kinase, and phosphoinositide-3 kinase signaling pathways. In homogenotypic and heterogenotypic cocultures of neurons and astrocytes, reduced neurite outgrowth was observed only if CHL1 was simultaneously present on both cell types. These findings and novel in vitro evidence for a homophilic CHL1-CHL1 interaction indicate that CHL1 is a glial scar component that restricts posttraumatic axonal growth and remodeling of spinal circuits by homophilic binding mechanisms.