Structural Modification of Fibroblast Growth Factor-binding Heparan Sulfate at a Determinative Stage of Neural Development*
- Yardenah G. Brickman‡,
- Miriam D. Ford,
- John T. Gallagher§,
- Victor Nurcombe,
- Perry F. Bartlett¶ and
- Jeremy E. Turnbull§‖
- From the Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia 3052, the ¶Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia 3050, and the §CRC Medical Oncology Department, University of Manchester, Christie CRC Research Centre, Manchester, M20 4BX United Kingdom
Abstract
Heparan sulfate (HS) glycosaminoglycans are essential modulators of fibroblast growth factor (FGF) activity and appear to act by coupling particular forms of FGF to appropriate FGF receptors. During neural development, one particular HS proteoglycan is able to rapidly switch its potentiating activity from FGF-2, as neural precursor cell proliferation occurs, to FGF-1, as neuronal differentiation occurs. Using various analytical techniques, including chemical and enzymatic cleavage, low pressure chromatography, and strong anion-exchange high performance liquid chromatography, we have analyzed the different HSs expressed during these crucial developmental stages. There are distinct alterations in patterns of 6-O-sulfation, total chain length, and the number of sulfated domains of the HS from the more mature embryonic brain. These changes correlate with a switch in the ability of the HS to potentiate the actions of FGF-1 in triggering cell differentiation. It thus appears that each HS pool is designed to function in the modulation of an intricate interaction with a specific growth factor and its cognate receptor, and suggests tightly regulated expression of specific, bioactive disaccharide sequences. The data can be used to construct a simple model of controlled variations in HS chain structure which have functional consequences at a crucial stage of neuronal maturation.
Footnotes
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↵* This work was supported in part by the National Health and Medical Research Council of Australia and the United Kingdom Cancer Research Campaign.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported by an Overseas Postgraduate Research Award and a Melbourne University Postgraduate Scholarship. To whom correspondence should be addressed: Van Cleef/Roet Centre for Nervous Diseases, Dept. of Medicine (Dept. of Neuroscience), Monash University, Alfred Hospital, Commercial Rd, Prahran. Victoria 3181, Australia. E-mail:Yardenah.Brickman{at}med.monash.edu.au; Tel.: 03-9276-2697; Fax: 9276-2458.
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↵‖ Present address: School of Biochemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom. E-mail:j.e.turnbull{at}bham.ac.uk.
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↵1 The abbreviations used are: FGF, fibroblast growth factor; HS, heparan sulfate; HSPGs, heparan sulfate proteoglycans; E10, embryonic day 10; SAX-HPLC, strong anion exchange-high pressure liquid chromatography; GlcA, glucuronic acid; AManR, reduced anhydromannose; IdoA, iduronic acid; GlcNAc, N-acetylated glucosamine; GlcNSO3,N-sulfated glucosamine; HexA, hexuronic acid.
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↵2 V. Nurcombe, S. J. Joseph, and Y. Brickman, unpublished data.
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- Received August 27, 1997.
- Revision received December 1, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
