Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury

Neurobiol Dis. 2017 Mar;99:24-35. doi: 10.1016/j.nbd.2016.12.010. Epub 2016 Dec 14.


Axon regeneration in the central nervous system is limited both by inhibitory extracellular cues and by an intrinsically low capacity for axon growth in some CNS populations. Chondroitin sulfate proteoglycans (CSPGs) are well-studied inhibitors of axon growth in the CNS, and degradation of CSPGs by chondroitinase has been shown to improve the extension of injured axons. Alternatively, axon growth can be improved by targeting the neuron-intrinsic growth capacity through forced expression of regeneration-associated transcription factors. For example, a transcriptionally active chimera of Krüppel-like Factor 7 (KLF7) and a VP16 domain improves axon growth when expressed in corticospinal tract neurons. Here we tested the hypothesis that combined expression of chondroitinase and VP16-KLF7 would lead to further improvements in axon growth after spinal injury. Chondroitinase was expressed by viral transduction of cells in the spinal cord, while VP16-KLF7 was virally expressed in sensory neurons of the dorsal root ganglia or corticospinal tract (CST) neurons. After transection of the dorsal columns, both chondroitinase and VP16-KLF7 increased the proximity of severed sensory axons to the injury site. Similarly, after complete crush injuries, VP16-KLF7 expression increased the approach of CST axons to the injury site. In neither paradigm however, did single or combined treatment with chondroitinase or VP16-KLF7 enable regenerative growth distal to the injury. These results substantiate a role for CSPG inhibition and low KLF7 activity in determining the net retraction of axons from sites of spinal injury, while suggesting that additional factors act to limit a full regenerative response.

Keywords: Adeno-associated virus; Axon regeneration; Chondroitin sulfate proteoglycan; Chondroitinase; Corticospinal; Dorsal root ganglion; KLF7; Lentivirus; Spinal cord injury; Transcription factor.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Chondroitin ABC Lyase / administration & dosage*
  • Chondroitin ABC Lyase / genetics
  • Chondroitin ABC Lyase / metabolism
  • Disease Models, Animal
  • Female
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Genetic Therapy
  • Genetic Vectors
  • HEK293 Cells
  • Humans
  • Kruppel-Like Transcription Factors / administration & dosage*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mice, Inbred C57BL
  • Mutant Chimeric Proteins / genetics
  • Mutant Chimeric Proteins / metabolism
  • Neuronal Outgrowth / physiology
  • Neurons, Afferent / metabolism*
  • Neurons, Afferent / pathology
  • Proteus vulgaris
  • Pyramidal Tracts / metabolism*
  • Pyramidal Tracts / pathology
  • Sciatic Nerve / injuries
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / therapy*


  • Bacterial Proteins
  • Kruppel-Like Transcription Factors
  • Mutant Chimeric Proteins
  • Chondroitin ABC Lyase