title: A sulfated carbohydrate epitope inhibits axon regeneration after injury.
abstract: Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTPσ, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-E-specific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Brown
authors.forename: Jiang
authors.initials: J
authors.lastname: Xia
authors.forename: BinQuan
authors.initials: B
authors.lastname: Zhuang
authors.forename: Kin-Sang
authors.initials: KS
authors.lastname: Cho
authors.forename: Claude J
authors.initials: CJ
authors.lastname: Rogers
authors.forename: Cristal I
authors.initials: CI
authors.lastname: Gama
authors.forename: Manish
authors.initials: M
authors.lastname: Rawat
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Tully
authors.forename: Noriko
authors.initials: N
authors.lastname: Uetani
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Mason
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Osami
authors.initials: O
authors.lastname: Habuchi
authors.forename: Dong F
authors.initials: DF
authors.lastname: Chen
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsieh-Wilson
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D002236:Carbohydrate Conformation; D002645:Chickens; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000276:immunology*; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000201:enzymology; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D011508:Chondroitin Sulfate Proteoglycans; D000939:Epitopes; D002809:Chondroitin Sulfates; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2