Wang, H1, Katagiri, Y.1,*, , McCann, T.E.1, Unsworth, E2, Goldsmith. P.2, Yu, Z.3, Tan, F.1, Santiago, L.1, Mills, E.M.4, Wang, Y5, Symes, A.J.5 and H.M. Geller1
1 Developmental Neurobiology Section, National Institutes of Health, Bethesda, MD 20892, USA
3 Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
4 Division of Pharmacology/Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA
5 Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Author for correspondence (e-mail: katagir@helix.nih.gov
)
Abstract
Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated chondroitin sulfate GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings show that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function.
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