Expression of an activated integrin promotes long-distance sensory axon regeneration in the spinal cord

Abstract

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 ?9?1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a ?1-binding integrin activator, kindlin-1. We examined the synergistic effect of ?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 ?9 integrin or kindlin-1 alone promoted much less regeneration and recovery

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ORCID for Melissa Andrews: orcid.org/0000-0001-5960-5619

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