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Extracellular Matrix of the Central Nervous System: from Neglect to Challenge

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Extracellular Matrix of the Central Nervous System: from Neglect to Challenge Histochem Cell Biol (2008) 130:635–653 DOI 10.1007/s00418-008-0485-9 REVIEW Extracellular matrix of the central nervous system: from neglect to challenge Dieter R. Zimmermann · María T. Dours-Zimmermann Accepted: 26 July 2008 / Published online: 12 August 2008 © Springer-Verlag 2008 Abstract The basic concept, that specialized extracellular Introduction matrices rich in hyaluronan, chondroitin sulfate proteogly- cans (aggrecan, versican, neurocan, brevican, phosphacan), It was not until 1971 that the existence of an extracellular link proteins and tenascins (Tn-R, Tn-C) can regulate cellu- matrix (ECM) in the central nervous system (CNS) was lar migration and axonal growth and thus, actively partici- generally acknowledged (Tani and Ametani 1971). Then a pate in the development and maturation of the nervous predominance of hyaluronan and chondroitin sulfate prote- system, has in recent years gained rapidly expanding experi- oglycans (CSPG) (Margolis et al. 1975) and the paucity of mental support. The swift assembly and remodeling of otherwise frequent ECM molecules, like Wbronectin or col- these matrices have been associated with axonal guidance lagens, have been described (Carbonetto 1984; Rutka et al. functions in the periphery and with the structural stabiliza- 1988; Sanes 1989). Today we know that this distinctive tion of myelinated Wber tracts and synaptic contacts in the ECM is mainly composed of proteoglycans of the lectican/ maturating central nervous system. Particular interest has hyalectan-family and their binding partners, hyaluronan, been focused on the putative role of chondroitin sulfate pro- link proteins and tenascins (Bandtlow and Zimmermann teoglycans in suppressing central nervous system regenera- 2000; Novak and Kaye 2000; Rauch 1997, 2004; Ruoslahti tion after lesions. The axon growth inhibitory properties of 1996; Yamaguchi 2000). In the following, we will focus on several of these chondroitin sulfate proteoglycans in vitro, the structure, expression and putative functions of this and the partial recovery of structural plasticity in lesioned major matrix components that form this extraordinary animals treated with chondroitin sulfate degrading enzymes extracellular meshwork. Not discussed in this review are in vivo have signiWcantly contributed to the increased less abundant, but nonetheless functionally important awareness of this long time neglected structure. macromolecules of the nervous system, such as reelin, agrin and thrombospondins. For detailed information about Keywords CSPG · Lectican · Hyalectan · ADAMTS · these large glycoproteins, which are involved in the control Hyaluronan synthase · Perineuronal net · Node of Ranvier · of neuronal migration and establishment of synapses we Knockout · Tenascin · Link protein · Central nervous would like to refer the reader to recent reviews and publica- system tions (Bezakova and Ruegg 2003; Christopherson et al. 2005; Herz and Chen 2006; Tissir and GoYnet 2003). Structures and ligands of the major constituents of the neural ECM D. R. Zimmermann (&) · M. T. Dours-Zimmermann Proteoglycans and hyaluronan Division of Diagnostic Molecular Pathology, Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland Proteoglycans (PGs) are glycoproteins carrying, in addition e-mail: [email protected]; [email protected] to variable numbers of N- and O-linked oligosaccharides, at 123 636 Histochem Cell Biol (2008) 130:635–653 least one glycosaminoglycan (GAG) side chain, which is giving rise to three HAS isoenzymes have been identiWed covalently bound to a core protein. The GAGs themselves (DeAngelis 1999; Itano and Kimata 2002; Spicer and are long unbranched polymers of repetitive disaccharide McDonald 1998; Weigel et al. 1997). The HAS are rather units consisting of an uronic acid (glucuronic or iduronic) unique, as they catalyze the incorporation of two diVerent or galactose and an amino-sugar (N-acetylglucosamine or monosaccharides and are, in contrast to most other glyco- N-acetylgalactosamine). According to the combination of syltransferases, localized at the inner surface of the cell these sugars, the GAGs are subclassiWed into heparin/hepa- membrane. From there the growing hyaluronan string ran-, keratan- or chondroitin/dermatan-sulfates (Bandtlow directly extrudes into the pericellular space, while being and Zimmermann 2000; Kjellén and Lindahl 1991; Prydz still attached to the producing enzyme (Spicer and Tien and Dalen 2000). The GAG chains are in general 20–200 2004; Weigel et al. 1997). disaccharide-repeats long. Whereas keratan sulfates are The most prominent binding partners of hyaluronan in usually attached to the core proteins via short standard N- the nervous system are the extracellular matrix proteogly- or O-glycan links to asparagine or serine/threonine, respec- cans of the lectican family (also called hyalectans) tively, the binding of chondroitin/dermatan sulfate and of (reviewed by Bandtlow and Zimmermann 2000; Iozzo and heparin/heparan sulfate chains is mediated by a serine resi- Murdoch 1996; Rauch 2004; Ruoslahti 1996; Yamaguchi due and a speciWc linker tetrasaccharide composed of a 2000). In mammals, four distinct lectican genes encode xylose, two consecutive galactoses and a glucuronic acid brevican, neurocan, aggrecan and versican (Table 1; molecule. Numerous modiWcations that include O- and N- Fig. 1). Shared features among these large chondroitin sul- sulfation and epimerization of glucuronic acid at the C5- fate proteoglycans are the highly homologous G1 and G3 position lead to a high structural variability and open up domains, which appear in rotary shadowing electron countless possibilities for the modulation of GAG-depen- microscopy as compact globular structures at either end of dent interactions (Bulow and Hobert 2006; Kusche-Gull- an extended, but Xexible central region (Mörgelin et al. berg and Kjellen 2003). Moreover, the highly negatively 1989; Retzler et al. 1996). This poorly sequence-conserved charged GAGs attract and bind considerable amount of middle part carries most of the O- and N-linked oligosac- water and cations. charides and all glycosaminoglycan side chains. It varies In contrast to the protein-bound GAGs, hyaluronan (also among the diVerent family members in size and also in the known as hyaluronic acid or hyaluronate) is incorporated number of carbohydrate substitutions. Occasionally, the into the extracellular matrix as a core protein-free glycos- GAGs might even be absent, like in a fraction of the part- aminoglycan (Toole 2000, 2004). Hyaluronan is a very time preoteoglycan brevican, or they may be greatly dimin- large linear polymer built of repetitive disaccharides units ished, as in CNS-derived aggrecan in relation to its carti- consisting of glucuronic acid and N-acetylglucosamine. lage counterpart. Apart from the variations within the This carbohydrate Wlament reaches a molecular mass of up carbohydrate moiety, alternative splicing also greatly adds to 107 Da and extends over lengths of 2–25 m. Unlike the to the structural diversity of lecticans. Four versican iso- other GAGs, hyaluronan is not sulfated and the glucuronic forms (V0, V1, V2 and V3) exist as a result of alternative acid units are not epimerized. usage of two giant exons encoding the central GAG- and While the more complex core protein-bound GAGs are GAG- domains (Dours-Zimmermann and Zimmermann assembled and modiWed by a large set of glycosyl- and sul- 1994; Zako et al. 1995; Zimmermann and Ruoslahti 1989). fotransferases, the structurally simpler hyaluronan is syn- Versican V0 contains both of these GAG-attachment mod- thesized by a single enzyme, the hyaluronan synthase ules, whereas versican V1 and V2 include only the GAG- (HAS). Three vertebrate genes (HAS1, HAS2, and HAS3) or GAG-, respectively. Versican V3, the smallest lectican, Table 1 Extracellular matrix Name Core sizea GAGs Cellular origin CNS- CSPGs in the central nervous speciWc system Calculatedb SDS-PAGEc Type Number Aggrecan 244 370 CS ? Neurons/astrocytes No Versican V0 371 t550 CS 17–23 Neurons/astrocytes? No Versican V1 263 t500 CS 12–15 Astrocytes? No a kDa Versican V2 180 400 CS 5–8 Oligodendroglial lineage Yes b Mature polypeptide Neurocan 141 245 CS 3 Astrocytes/neurons Yesd c Core glycoprotein after gly- cosaminoglycan removal Brevican 97 145 CS 0–5 Glial cells/neurons Yes d Minor expression in peripheral Phosphacan 172 400 CS/(KS) 3–4 Glial cells/neurons Yes nervous system (-KS) 123 Histochem Cell Biol (2008) 130:635–653 637 Fig. 1 Structural models of the chondroitin sulfate proteoglycans of the lectican family. ADAMTS cleavage sites and binding regions of the poly- clonal antibodies used in immunohistochemical stainings displayed in the following Wgures are indicated lacks both of these alternatively spliced elements and con- Besides the large aggregating proteoglycans of the lecti- sequently carries no glycosaminoglycans. can family, phosphacan, a secreted CSPG-isoform of the In contrast to these largely diversiWed GAG-binding receptor-type protein-tyrosine phosphatase (RPTP), regions, the modules that form the globular G1 and G3 plays a prominent role in the brain ECM (Barnea et al. structures display little variability. For instance, all N-ter- 1994; Maurel et al. 1994; Shitara et al. 1994). Like the minal G1 regions of the diVerent lecticans include an other alternative splice products of the RPTP gene, it is immunoglobulin (Ig)-like loop and two link-protein-like composed of a carbonic anhydrase
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