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Specific heparan sulfate structures involved in retinal axon targeting

Atsushi Irie^1,*, Edwin A. Yates², Jeremy E. Turnbull^2, and Christine E. Holt^1,

¹ Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
² Molecular Cell Biology Research Laboratories, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
^* Present address: The Tokyo Metropolitan Institute of Medical Science, Department of Biochemical Cell Research, Bunkyo-ku, Tokyo 113-8613, Japan

Authors for correspondence (e-mail: ceh{at}mole.bio.cam.ac.uk and j.e.turnbull@bham.ac.uk">j.e.turnbull@bham.ac.uk)

Accepted 8 October 2001

Heparan sulfate (HS), a structurally diverse molecule comprising distinct sequences of sulfated disaccharide units, is abundant in the developing brain and binds to axon guidance molecules. Addition of HS to the developing Xenopus optic pathway causes severe targeting errors yet it is not known how the structural diversity of this molecule relates to its role in axon guidance. We have used an in vivo brain assay to identify the structural characteristics of HS that induce aberrant axon targeting. Inhibiting sulfation of endogenous HS with chlorate causes axons to bypass their target, the tectum, and treatment with chemically modified heparins reveals that 2-O- and 6-O-sulfate groups have potent bypass-inducing activity. Experiments with purified heparin saccharides show that bypass-inducing activity correlates with distinct structures, particularly those containing a combination of 2-O- and 6-O-sulfate groups. Taken together the results indicate that specific sequences, rather than gross structural composition, are critical for activity. In situ hybridisation revealed that HS 6-O-sulfotransferase is regionally expressed along the border of the dorsal optic tract whereas 2-O-sulfotransferase is expressed broadly. Our results demonstrate that specific HS sequences are essential for regulating retinotectal axon targeting and suggest that regionalised biosynthesis of specific HS structures is important for guiding axons into the tectum.

Key words: Axon guidance, Glycosaminoglycan, Heparan sulfate, Retinal axon, Sulfotransferase, Xenopus.

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