Hang Wang, Yasuhiro Katagiri, Thomas E. McCann, Edward Unsworth, Paul Goldsmith, Zu-Xi Yu, Fei Tan, Edward M. Mills, Yu Wang, Aviva J. Symes, and Herbert M. Geller

Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with an unparalleled diversity of biological regulatory properties based upon the length, composition, and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that a specific pattern of sulfation in the GAG chains of chondroitin sulfate (CS) 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 and activates RhoA. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated CS 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 provide the evidence for a "sulfation code" in which discrete sulfation motifs along the carbohydrate backbone carry instructions to regulate neuronal function.

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Dr. Herbert Geller, Head
Developmental Neurobiology Section, NHLBI, NIH
Building 10, Room 6D18, 10 Center Drive, MSC-1754
Bethesda, MD 20892
Email: gellerh@nhlbi.nih.gov

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