1992). The expression patterns of CS-PGs are altered in the adult CNS. the normal CNS. The findings suggest exciting EPI-001 prospects for enhancing growth and plasticity in the adult CNS; however, some protective roles of CS-PGs in the CNS have also been exhibited. Clearly many questions concerning the mechanisms regulating expression of extracellular matrix molecules in CNS pathology remain to be clarified. and studies to demonstrate axonal growth-inhibitory properties. More importantly, many of these molecules are specific to, or up-regulated in, the injured CNS environment. The molecules may be loosely classified into two main types: myelin-associated molecules and ECM constituents. Myelin-associated moleculesIn the late 1980s Schwab and colleagues demonstrated that a substrate non-permissive to growth exists in CNS white matter (Schwab & Thoenen, 1985; Schwab & Caroni, 1988; Crutcher, 1989; Savio & Schwab, 1989), leading to the hypothesis that where myelinated axons are disrupted, debris made up of myelin-associated axon-inhibitory molecules will be present around the lesion. A number of myelin-associated molecules have since been isolated that have axon-inhibitory properties, including the two neurite growth inhibitors Nogo (originally called NI-250) and myelin-associated glycoprotein (MAG). Much literature has been published recently concerning MAG, Nogo and the Nogo receptor (Nogo-66) that is beyond the scope of this article; for recent reviews see Bandtlow (2003) and McGee & Strittmatter (2003). ECM constituentsFor many neurons, their migration and axon elongation occurs through the ECM: in the CNS the ECM is largely devoid EPI-001 of cells but contains several types of molecules with which neurons and glia interact, and these can have important influences on many aspects of a cell’s behaviour. The extracellular space surrounding many non-neuronal cells in the CNS is filled with a network of glycoproteins, proteoglycans and hyaluronan; close to the membrane of such cells the ECM becomes more IgM Isotype Control antibody (FITC) dense, forming a basement membrane composed principally of collagens; glycoproteins C particularly tenascin-C and tenascin-R; chondroitin sulphate proteoglycans (CS-PGs) and heparan sulphate proteoglycans (HS-PGs); hyaluronic acid (HA); cell adhesion molecules and integrins. ECM molecules expressed in the developing CNS may have both growth-promoting and growth-inhibitory effects on axons (e.g. Snow et al. 1990b; Oakley & Tosney, 1991; Brittis et al. 1992; Emerling & Lander, 1996; Treloar et al. 1996; for review see Margolis & Margolis, 1997). Many of these molecules are up-regulated in the adult ECM following a lesion to the CNS (in particular CS-PGs; see below), and have been shown to have inhibitory properties towards regenerating axons. Tenascin is EPI-001 an important secreted ECM component with a range of binding sites and functions (Hoffman et al. 1988; Steindler et al. 1989; Grumet et al. 1994; Husmann et al. 1995; for review see Faissner, 1997). Tenascin is abundant in the basement membrane, being produced by astrocytes during development, with important roles in mediating axonCglia interactions (Steindler et al. 1989; Faissner & Kruse, 1990; Lochter et al. 1991). There are two members of the tenascin gene family: tenascin-C and tenascin-R; tenascin-C is expressed as EPI-001 numerous alternatively spliced variants with various functions (Faissner et al. 1988; Stern et al. 1989; Chuong & Chen, 1991; Faissner, 1997). The same tenascin molecule may have either growth-inhibitory EPI-001 or growth-promoting effects towards different neurons within different contexts; a number of studies have demonstrated the neurite growth-inhibitory properties of tenascin (Pesheva et al. 1989; Crossin et al. 1990; Faissner & Kruse, 1990). It also has growth-promoting effects ascribed to the alternatively spliced A-D and D5 domains (Meiners et al. 1999, 2001). Tenascin is found in the normal adult CNS although at lower levels than in the developing CNS. Production is up-regulated in the glial scar after injury (Laywell et al. 1992); the increased tenascin has been co-localized with reactive glial fibrillary acidic protein (GFAP)+ astrocytes (Lochter et al. 1991; McKeon et al. 1991; Laywell et al. 1992). Tenascin is known to interact with many CS-PGs (Grumet et al. 1994; Xiao et al. 1997, 1998), and thus may be capable of forming (axon-inhibitory) complexes with CS-PGs in injured CNS tissue..
