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
Date
12/19/2016Pubmed ID
27988344Pubmed Central ID
PMC5715811DOI
10.1016/j.nbd.2016.12.010Scopus ID
2-s2.0-85007572075 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
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.
Author List
Wang Z, Winsor K, Nienhaus C, Hess E, Blackmore MGAuthor
Murray Blackmore PhD Assistant Professor in the School of Allied Health department at Marquette UniversityMESH terms used to index this publication - Major topics in bold
AnimalsAxons
Bacterial Proteins
Chondroitin ABC Lyase
Disease Models, Animal
Female
Ganglia, Spinal
Genetic Therapy
Genetic Vectors
HEK293 Cells
Humans
Kruppel-Like Transcription Factors
Mice, Inbred C57BL
Mutant Chimeric Proteins
Neuronal Outgrowth
Neurons, Afferent
Proteus vulgaris
Pyramidal Tracts
Sciatic Nerve
Spinal Cord Injuries