α9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration
α9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration
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DOI：
10.1523/jneurosci.0759-09.2009
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发表时间：
2009-04-29
影响因子：
5.3
通讯作者：
Fawcett, James W.
中科院分区：
文献类型：
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作者：
Andrews, Melissa R.;Czvitkovich, Stefan;Fawcett, James W.
受损的中枢神经系统轴突在包含许多抑制因子的环境中被阻止再生。它们也缺乏与中枢神经系统主要的细胞外基质糖蛋白tenascin-C相互作用的整合素，后者在损伤后上调。α9β1整合素异二聚体是Tenascin-C非选择性剪接区的受体，但α9亚单位在成年神经元中缺失。在本研究中，我们发现PC12细胞和成年大鼠背根神经节(DRG)神经元在Tenascin-C上不延伸突起。然而，在强制表达α9整合素后，PC12细胞和成年大鼠背根神经节神经元出现了广泛的轴突生长。此外，DRG神经元和PC12细胞都会分泌Tenascin-C，使转Alpha 9基因的细胞能够在组织培养塑料上生长轴突。用腺相关病毒在DRG中活体表达α9整合素，我们观察了成年大鼠颈后根切断或背柱挤压后的轴突再生。损伤后6周，α9整合素表达组大鼠背根轴突明显多于绿色荧光蛋白(GFP)对照组。同样，背柱挤压伤后6周，与GFP对照组相比，损伤部位有明显更多的轴突生长。脊髓损伤后的行为学分析显示，与假手术组相比，实验组和对照组对机械刺激的戒断潜伏期均有延长；然而，在热刺激的反应下，α9整合素治疗组恢复了正常的戒断潜伏期，但对照组的戒断潜伏期仍高于对照组。
Damaged CNS axons are prevented from regenerating by an environment containing many inhibitory factors. They also lack an integrin that interacts with tenascin-C, the main extracellular matrix glycoprotein of the CNS, which is upregulated after injury. The alpha 9 beta 1 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the alpha 9 subunit is absent in adult neurons. In this study, we show that PC12 cells and adult rat dorsal root ganglion (DRG) neurons do not extend neurites on tenascin-C. However, after forced expression of alpha 9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling alpha 9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express alpha 9 integrin in vivo in DRGs, we examined axonal regeneration after cervical dorsal rhizotomy or dorsal column crush in the adult rat. After rhizotomy, significantly more dorsal root axons regrew into the dorsal root entry zone at 6 weeks after injury in alpha 9 integrin-expressing animals than in green fluorescent protein (GFP) controls. Similarly, after a dorsal column crush injury, there was significantly more axonal growth into the lesion site compared with GFP controls at 6 weeks after injury. Behavioral analysis after spinal cord injury revealed that both experimental and control groups had an increased withdrawal latency in response to mechanical stimulation when compared with sham controls; however, in response to heat stimulation, normal withdrawal latencies returned after alpha 9 integrin treatment but remained elevated in control groups.