Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans.
Axotomized neurons within the damaged CNS are thought to be prevented from functional regeneration by inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors. Here, we provide a transgenic test of the role of CSPGs in limiting regeneration, using the gfap promotor to express a CSPG-degrading enzyme chondroitinase ABC (ChABC) in astrocytes. Corticospinal axons extend within the lesion site, but not caudal to it, after dorsal hemisection in the transgenic mice. The presence of the gfap-ChABC transgene yields no significant improvement in motor function recovery in this model. In contrast, functionally significant sensory axon regeneration is observed after dorsal rhizotomy in transgenic mice. These transgenic studies confirm a local efficacy for reduced CSPG to enhance CNS axon growth after traumatic injury. CSPGs appear to function in a spatially distinct role from myelin inhibitors, implying that combination-based therapy will be especially advantageous for CNS injuries.
Cafferty
William B J
WB
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Yang
Shih-Hung
SH
Duffy
Philip J
PJ
Li
Shuxin
S
Strittmatter
Stephen M
SM
D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001369:Axons / Q000502:physiology*; D019765:Chondroitin ABC Lyase / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D002921:Cicatrix / Q000503:physiopathology; D005260:Female; D005552:Forelimb; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000235:genetics*; D010147:Pain Measurement; D019051:Rhizotomy; D012677:Sensation / Q000502:physiology; D012867:Skin / Q000294:innervation; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D013904:Thoracic Vertebrae; D015854:Up-Regulation
D011508:Chondroitin Sulfate Proteoglycans; D019765:Chondroitin ABC Lyase