Advertisement

Neurochemical Research

, Volume 36, Issue 7, pp 1228–1240 | Cite as

Functions of Chondroitin Sulfate and Heparan Sulfate in the Developing Brain

  • N. Maeda
  • M. Ishii
  • K. Nishimura
  • K. Kamimura
Original Paper
First Online:
Accepted:

Abstract

Chondroitin sulfate and heparan sulfate proteoglycans are major components of the cell surface and extracellular matrix in the brain. Both chondroitin sulfate and heparan sulfate are unbranched highly sulfated polysaccharides composed of repeating disaccharide units of glucuronic acid and N-acetylgalactosamine, and glucuronic acid and N-acetylglucosamine, respectively. During their biosynthesis in the Golgi apparatus, these glycosaminoglycans are highly modified by sulfation and C5 epimerization of glucuronic acid, leading to diverse heterogeneity in structure. Their structures are strictly regulated in a cell type-specific manner during development partly by the expression control of various glycosaminoglycan-modifying enzymes. It has been considered that specific combinations of glycosaminoglycan-modifying enzymes generate specific functional microdomains in the glycosaminoglycan chains, which bind selectively with various growth factors, morphogens, axon guidance molecules and extracellular matrix proteins. Recent studies have begun to reveal that the molecular interactions mediated by such glycosaminoglycan microdomains play critical roles in the various signaling pathways essential for the development of the brain.

Keywords

Brain Chondroitin sulfate Heparan sulfate Neuron Proteoglycan 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Bandtlow CE, Zimmermann DR (2000) Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 80:1267–1290PubMedGoogle Scholar
  2. 2.
    Maeda N (2010) Structural variation of chondroitin sulfate and its roles in the central nervous system. Cent Nerv Syst Agents Med Chem 10:22–31PubMedGoogle Scholar
  3. 3.
    Maeda N, Fukazawa N, Ishii M (2010) Chondroitin sulfate proteoglycans in neural development and plasticity. Front Biosci 15:626–644PubMedCrossRefGoogle Scholar
  4. 4.
    Watanabe H, Kimata K (2008) Chondroitin sulfate biosynthesis and related genes. In: Taniguchi N, Suzuki A, Ito Y et al (eds) Experimental glycoscience. Springer, Tokyo, pp 64–66CrossRefGoogle Scholar
  5. 5.
    Izumikawa T, Koike T, Shiozawa S et al (2008) Identification of chondroitin sulfate glucuronyltransferase as chondroitin synthase-3 involved in chondroitin polymerization: chondroitin polymerization is achieved by multiple enzyme complexes consisting of chondroitin synthase family members. J Biol Chem 283:11396–11406PubMedCrossRefGoogle Scholar
  6. 6.
    Sakai K, Kimata K, Sato T et al (2007) Chondroitin sulfate N-acetylgalactosaminyltransferase-1 plays a critical role in chondroitin sulfate synthesis in cartilage. J Biol Chem 282:4152–4161PubMedCrossRefGoogle Scholar
  7. 7.
    Mizumoto S, Kitagawa H (2008) Heparan sulfate synthases and related genes. In: Taniguchi N, Suzuki A, Ito Y et al (eds) Experimental glycoscience. Springer, Tokyo, pp 59–63CrossRefGoogle Scholar
  8. 8.
    Busse M, Feta A, Presto J et al (2007) Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation. J Biol Chem 282:32802–32810PubMedCrossRefGoogle Scholar
  9. 9.
    Habuchi O (2008) Sulfotransferases involved in sulfation of glycosaminoglycans. In: Taniguchi N, Suzuki A, Ito Y et al (eds) Experimental glycoscience. Springer, Tokyo, pp 87–93CrossRefGoogle Scholar
  10. 10.
    Ishii M, Maeda N (2008) Spatiotemporal expression of chondroitin sulfate sulfotransferases in the postnatal developing mouse cerebellum. Glycobiology 18:602–614PubMedCrossRefGoogle Scholar
  11. 11.
    Pacheco B, Malmstrom A, Maccarana M (2009) Two dermatan sulfate epimerases form iduronic acid domains in dermatan sulfate. J Biol Chem 284:9788–9795PubMedCrossRefGoogle Scholar
  12. 12.
    Yabe T, Hata T, He J et al (2005) Developmental and regional expression of heparan sulfate sulfotransferase genes in the mouse brain. Glycobiology 15:982–993PubMedCrossRefGoogle Scholar
  13. 13.
    Tekotte H, Engel M, Margolis RU et al (1994) Disaccharide composition of heparan sulfates: brain nervous tissue storage organelles, kidney, and lung. J Neurochem 62:1126–1130PubMedCrossRefGoogle Scholar
  14. 14.
    Mitsunaga C, Mikami T, Mizumoto S et al (2006) Chondroitin sulfate/dermatan sulfate hybrid chains in the development of cerebellum. Spatiotemporal regulation of the expression of critical disulfated disaccharides by specific sulfotransferases. J Biol Chem 281:18942–18952PubMedCrossRefGoogle Scholar
  15. 15.
    Akita K, Holst A, Furukawa Y et al (2008) Expression of multiple chondroitin/dermatan sulfotransferases in the neurogenic regions of the embryonic and adult CNS imply that complex chondroitin sulfates have a role in neural stem cell maintenance. Stem Cells 26:798–809PubMedCrossRefGoogle Scholar
  16. 16.
    Ishii M, Maeda N (2008) Oversulfated chondroitin sulfate plays critical roles in the neuronal migration in the cerebral cortex. J Biol Chem 283:32610–32620PubMedCrossRefGoogle Scholar
  17. 17.
    Habuchi H, Suzuki S, Saito T et al (1992) Structure of a heparan sulphate oligosaccharide that binds to basic fibroblast growth factor. Biochem J 285:805–813PubMedGoogle Scholar
  18. 18.
    Ashikari-Hada S, Habuchi H, Kariya Y et al (2004) Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J Biol Chem 279:12346–12354PubMedCrossRefGoogle Scholar
  19. 19.
    Maeda N, He J, Yajima Y et al (2003) Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/heparin binding growth-associated molecule. J Biol Chem 278:35805–35811PubMedCrossRefGoogle Scholar
  20. 20.
    Bao X, Nishimura S, Mikami T et al (2004) Chondroitin sulfate/dermatan sulfate hybrid chains from embryonic pig brain, which contain a higher proportion of l-iduronic acid than those from adult pig brain, exhibit neuritogenic and growth factor binding activities. J Biol Chem 279:9765–9776PubMedCrossRefGoogle Scholar
  21. 21.
    Bao X, Mikami T, Yamada S et al (2005) Heparin-binding growth factor, pleiotrophin, mediates neuritogenic activity of embryonic pig brain-derived chondroitin sulfate/dermatan sulfate hybrid chains. J Biol Chem 280:9180–9191PubMedCrossRefGoogle Scholar
  22. 22.
    Oohira A, Matsui F, Watanabe E et al (1994) Developmentally regulated expression of a brain specific species of chondroitin sulfate proteoglycan, neurocan, identified with a monoclonal antibody 1G2 in the rat cerebrum. Neuroscience 60:145–157PubMedCrossRefGoogle Scholar
  23. 23.
    Watanabe E, Maeda N, Matsui F et al (1995) Neuroglycan C, a novel membrane-spanning chondroitin sulfate proteoglycan that is restricted to the brain. J Biol Chem 270:26876–26882PubMedCrossRefGoogle Scholar
  24. 24.
    Aono S, Keino H, Ono T et al (2000) Genomic organization and expression pattern of mouse neuroglycan C in the cerebellar development. J Biol Chem 275:337–342PubMedCrossRefGoogle Scholar
  25. 25.
    Lambaerts K, Wilcox-Adelman SA, Zimmermann P (2009) The signaling mechanism of syndecan heparan sulfate proteoglycans. Curr Opin Cell Biol 21:662–669PubMedCrossRefGoogle Scholar
  26. 26.
    Litwack ED, Stipp CS, Kumbasar A et al (1994) Neuronal expression of glypican, a cell-surface glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan, in the adult rat nervous system. J Neurosci 14:3713–3724PubMedGoogle Scholar
  27. 27.
    Filmus J, Capurro M, Rast J (2008) Glypicans. Genome Biol 9:224PubMedCrossRefGoogle Scholar
  28. 28.
    Miller JD, Cummings J, Maresh GA et al (1997) Localization of perlecan (or a perlecan-related macromolecule) to isolated microglia in vitro and to microglia/macrophages following infusion of beta-amyloid protein into rodent hippocampus. Glia 21:228–243PubMedCrossRefGoogle Scholar
  29. 29.
    Shipp EL, Hsieh-Wilson LC (2007) Profiling the sulfation specificities of glycosaminoglycan interactions with growth factors and chemotactic proteins using microarrays. Chem Biol 14:195–208PubMedCrossRefGoogle Scholar
  30. 30.
    Deepa SS, Umehara Y, Higashiyama S et al (2002) Specific molecular interactions of oversulfated chondroitin sulfate E with various heparin-binding growth factors. J Biol Chem 277:43707–43716PubMedCrossRefGoogle Scholar
  31. 31.
    Maeda N, Fukazawa N, Hata T (2006) The binding of chondroitin sulfate to pleiotrophin/heparin-binding growth-associated molecule is regulated by chain length and oversulfated structures. J Biol Chem 281:4894–4902PubMedCrossRefGoogle Scholar
  32. 32.
    Deepa SS, Kalayanamitra K, Ito Y et al (2007) Novel sulfated octa- and decasaccharides from squid cartilage chondroitin sulfate E: sequencing and application for determination of the epitope structures of the monoclonal antibody MO-225. Biochemistry 46:2453–2465PubMedCrossRefGoogle Scholar
  33. 33.
    Mikami T, Yasunaga D, Kitagawa H (2009) Contactin-1 is a functional receptor for neuroregulatory chondroitin sulfate-E. J Biol Chem 284:4494–4499PubMedCrossRefGoogle Scholar
  34. 34.
    Lin X, Wei G, Shi Z et al (2000) Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Dev Biol 224:299–311PubMedCrossRefGoogle Scholar
  35. 35.
    Okada M, Nadanaka S, Shoji N et al (2010) Biosynthesis of heparan sulfate in EXT1-deficient cells. Biochem J 428:463–471PubMedCrossRefGoogle Scholar
  36. 36.
    Izumikawa T, Kanagawa N, Wakamoto Y et al (2010) Impairment of embryonic cell division and glycosaminoglycan biosynthesis in glucuronyltransferase-I-deficient mice. J Biol Chem 285:12190–12196PubMedCrossRefGoogle Scholar
  37. 37.
    Inatani M, Irie F, Plump AS et al (2003) Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science 302:1044–1046PubMedCrossRefGoogle Scholar
  38. 38.
    Grobe K, Inatani M, Pallerla SR et al (2005) Cerebral hypoplasia and craniofacial defects in mice lacking heparan sulfate Ndst1 gene function. Development 132:3777–3786PubMedCrossRefGoogle Scholar
  39. 39.
    Bullock SL, Fletcher JM, Beddington RSP et al (1998) Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev 12:1894–1906PubMedCrossRefGoogle Scholar
  40. 40.
    McLaughlin D, Karlsson F, Tian N et al (2003) Specific modification of heparan sulfate is required for normal cerebral cortical development. Mech Dev 120:1481–1488PubMedCrossRefGoogle Scholar
  41. 41.
    Pratt T, Conway CD, Tian NM et al (2006) Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm. J Neurosci 26:6911–6923PubMedCrossRefGoogle Scholar
  42. 42.
    Merry CLR, Bullock SL, Swan DC et al (2001) The molecular phenotype of heparan sulfate in the Hs2st−/− mutant mice. J Biol Chem 276:35429–35434PubMedCrossRefGoogle Scholar
  43. 43.
    Habuchi H, Nagai N, Sugaya N et al (2007) Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality. J Biol Chem 282:15578–15588PubMedCrossRefGoogle Scholar
  44. 44.
    Bernhardt RR, Schachner M (2000) Chondroitin sulfates affect the formation of the segmental motor nerves in zebrafish embryos. Dev Biol 221:206–219PubMedCrossRefGoogle Scholar
  45. 45.
    Chung KY, Taylor JSH, Shum DKY et al (2000) Axon routing at the optic chiasm after enzymatic removal of chondroitin sulfate in mouse embryos. Development 127:2673–2683PubMedGoogle Scholar
  46. 46.
    Ichijo H, Kawabata I (2001) Roles of the telencephalic cells and their chondroitin sulfate proteoglycans in delimiting an anterior border of the retinal pathway. J Neurosci 21:9304–9314PubMedGoogle Scholar
  47. 47.
    Ichijo H (2006) Restricted distribution of D-unit-rich chondroitin sulfate carbohydrate chains in the neuropil encircling the optic tract and on a subset of retinal axons in chick embryos. J Comp Neurol 495:470–479PubMedCrossRefGoogle Scholar
  48. 48.
    Kantor DB, Chivatakarn O, Peer KL et al (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975PubMedCrossRefGoogle Scholar
  49. 49.
    Pizzorusso T, Medini P, Berardi N et al (2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298:1248–1251PubMedCrossRefGoogle Scholar
  50. 50.
    Moon LDF, Asher RA, Rhodes KE et al (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci 4:465–466PubMedGoogle Scholar
  51. 51.
    Bradbury EJ, Moon LDF, Popat RJ et al (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416:636–640PubMedCrossRefGoogle Scholar
  52. 52.
    Carter LM, Starkey ML, Akrimi SF et al (2008) The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. J Neurosci 28:14107–14120PubMedCrossRefGoogle Scholar
  53. 53.
    Oohira A, Matsui F, Matsuda M et al (1986) Developmental change in the glycosaminoglycan composition of the rat brain. J Neurochem 47:588–593PubMedCrossRefGoogle Scholar
  54. 54.
    Nishimura K, Ishii M, Kuraoka M et al (2010) Opposing functions of chondroitin sulfate and heparan sulfate during early neuronal polarization. Neuroscience 169:1535–1547PubMedCrossRefGoogle Scholar
  55. 55.
    Shimazaki Y, Nagata I, Ishii M et al (2005) Developmental change and function of chondroitin sulfate deposited around cerebellar Purkinje cells. J Neurosci Res 82:172–183PubMedCrossRefGoogle Scholar
  56. 56.
    Ida M, Shuo T, Hirano K et al (2006) Identification and functions of chondroitin sulfate in the milieu of neural stem cells. J Biol Chem 281:5982–5991PubMedCrossRefGoogle Scholar
  57. 57.
    Sirko S, Holst A, Weber A et al (2010) Chondroitin sulfate are required for fibroblast growth factor-2-dependent proliferation and maintenance in neural stem cells and for epidermal growth factor-dependent migration of their progeny. Stem Cells 28:775–787PubMedCrossRefGoogle Scholar
  58. 58.
    Maeda N, Noda M (1998) Involvement of receptor-like protein tyrosine phosphatase ζ/RPTPβ and its ligand pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) in neuronal migration. J Cell Biol 142:203–216PubMedCrossRefGoogle Scholar
  59. 59.
    Maeda N, Nishiwaki T, Shintani T et al (1996) 6B4 proteoglycan/phosphacan, an extracellular variant of receptor-like protein-tyrosine phosphatase ζ/RPTPβ, binds pleiotrophin/heparin-binding growth-associated molecule (HB-GAM). J Biol Chem 271:21446–21452PubMedCrossRefGoogle Scholar
  60. 60.
    Maeda N, Ichihara-Tanaka K, Kimura T et al (1999) A receptor-like protein-tyrosine phosphatase PTPζ/RPTPβ binds a heparin-binding growth factor midkine. J Biol Chem 274:12474–12479PubMedCrossRefGoogle Scholar
  61. 61.
    Maeda N, Matsui F, Oohira A (1992) A chondroitin sulfate proteoglycan that is developmentally regulated in the cerebellar mossy fiber system. Dev Biol 151:564–574PubMedCrossRefGoogle Scholar
  62. 62.
    Tanaka M, Maeda N, Noda M et al (2003) A chondroitin sulfate proteoglycan PTPζ/RPTPβ regulates the morphogenesis of Purkinje cell dendrites in the developing cerebellum. J Neurosci 23:2804–2814PubMedGoogle Scholar
  63. 63.
    Fukazawa N, Yokoyama S, Eiraku M et al (2008) Receptor type protein tyrosine phosphatase ζ-pleiotrophin signaling controls endocytic trafficking of DNER that regulates neuritogenesis. Mol Cell Biol 28:4494–4506PubMedCrossRefGoogle Scholar
  64. 64.
    Matsumoto K, Wanaka A, Takatsuji K et al (1994) A novel family of heparin-binding growth factors, pleiotrophin and midkine, is expressed in the rat cerebral cortex. Dev Brain Res 79:229–241CrossRefGoogle Scholar
  65. 65.
    Tabata H, Nakajima K (2003) Multipolar migration: the third mode of radial neuronal migration in the developing cerebral cortex. J Neurosci 23:9996–10001PubMedGoogle Scholar
  66. 66.
    Arimura N, Kaibuchi K (2007) Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci 8:194–205PubMedCrossRefGoogle Scholar
  67. 67.
    Barnes AP, Polleux F (2009) Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci 32:347–381PubMedCrossRefGoogle Scholar
  68. 68.
    Dotti CG, Sullivan CA, Banker GA (1988) The establishment of polarity by hippocampal neurons in culture. J Neurosci 8:1454–1468PubMedGoogle Scholar
  69. 69.
    Yamagata M, Kimata K, Oike Y et al (1987) A monoclonal antibody that specifically recognizes a glucuronic acid 2-sulfate-containing determinant in intact chondroitin sulfate chain. J Biol Chem 262:4146–4152PubMedGoogle Scholar
  70. 70.
    Born J, Salmivirta K, Henttinen T et al (2005) Novel heparan sulfate structures revealed by monoclonal antibodies. J Biol Chem 280:20516–20524PubMedCrossRefGoogle Scholar
  71. 71.
    Muramatsu H, Zou P, Suzuki H et al (2004) α4β1- and α6β1-integrins are functional receptors for midkine, a heparin-binding growth factor. J Cell Sci 117:5405–5415PubMedCrossRefGoogle Scholar
  72. 72.
    Mikelis C, Sfaelou E, Koutsioumpa M et al (2009) Integrin αvβ3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase β/ζ. FASEB J 23:1459–1469PubMedCrossRefGoogle Scholar
  73. 73.
    Yang J, Price MA, Neudauer CL et al (2004) Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms. J Cell Biol 165:881–891PubMedCrossRefGoogle Scholar
  74. 74.
    Iida J, Meijine AML, Oegema TR et al (1998) A role of chondroitin sulfate glycosaminoglycan binding site in α4β1 integrin-mediated melanoma cell adhesion. J Biol Chem 273:5955–5962PubMedCrossRefGoogle Scholar
  75. 75.
    Chen Z-L, Haegeli V, Yu H et al (2009) Cortical deficiency of laminin γ1 impairs the AKT/GSK-3β signaling pathway and leads to defects in neurite outgrowth and neuronal migration. Dev Biol 327:158–168PubMedCrossRefGoogle Scholar
  76. 76.
    Hu H (2001) Cell surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein. Nat Neurosci 4:695–701PubMedCrossRefGoogle Scholar
  77. 77.
    Irie F, Okuno M, Matsumoto K et al (2008) Heparan sulfate regulates ephrin-A3/EphA receptor signaling. Proc Natl Acad Sci USA 105:12307–12312PubMedCrossRefGoogle Scholar
  78. 78.
    Hussain S, Piper M, Fukuhara N et al (2006) A molecular mechanism for the heparan sulfate dependence of Slit-Robo signaling. J Biol Chem 281:39693–39698PubMedCrossRefGoogle Scholar
  79. 79.
    Steigemann P, Molitor A, Fellert S et al (2004) Heparan sulfate proteoglycan syndecan promotes axonal and myotube guidance by slit/robo signaling. Curr Biol 14:225–230PubMedGoogle Scholar
  80. 80.
    Ronca F, Anderson JS, Paech V et al (2001) Characterization of Slit protein interactions with glypican-1. J Biol Chem 276:29141–29147PubMedCrossRefGoogle Scholar
  81. 81.
    Ethell IM, Irie F, Kalo MS et al (2001) EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31:1001–1013PubMedCrossRefGoogle Scholar
  82. 82.
    Deepa SS, Carulli D, Galtrey C et al (2006) Composition of perineuronal net extracellular matrix in rat brain. J Biol Chem 281:17789–17800PubMedCrossRefGoogle Scholar
  83. 83.
    Lander C, Kind P, Maleski M et al (1997) A family of activity-dependent neuronal cell-surface chondroitin sulfate proteoglycans in cat visual cortex. J Neurosci 17:1928–1939PubMedGoogle Scholar
  84. 84.
    Sugiyama S, Nardo A, Aizawa S et al (2008) Experience-dependent transfer of Otx2 homeoprotein into visual cortex activities postnatal plasticity. Cell 134:508–520PubMedCrossRefGoogle Scholar
  85. 85.
    Gogolla N, Caroni P, Luthi A et al (2009) Perineuronal nets protect fear memorie from erasure. Science 325:1258–1261PubMedCrossRefGoogle Scholar
  86. 86.
    Carulli D, Pizzorusso T, Kwok JCF et al (2010) Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133:2331–2347PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Developmental NeuroscienceTokyo Metropolitan Institute for NeuroscienceFuchu, TokyoJapan

Personalised recommendations