期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 27, 页码 7283-7297出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0901-16.2016
关键词
adeno-associated virus; alpha9 integrin; axon regeneration; dorsal root ganglion; kindlin-1; spinal cord
资金
- Christopher and Dana Reeve Foundation
- Medical Research Council
- European Research Council ECMneuro
- Medical Research Council Biomedical Research Centre
- Acorda Therapeutics
- Novartis
- Cambridge National Health
- MRC [G1000864] Funding Source: UKRI
- International Spinal Research Trust [NRB110] Funding Source: researchfish
- Medical Research Council [G1000864] Funding Source: researchfish
After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly alpha 9 beta 1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a beta 1-binding integrin activator, kindlin-1. We examined the synergistic effect of alpha 9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of alpha 9 integrin or kindlin-1 alone promoted much less regeneration and recovery.
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