The differentiating R428 mouse step between synthesis of chondroitin suphate and dermatan sulphate GAGs is the epimerization of GlcA to its stereoisomer iduronic acid, whereby the presence of iduronic acid confers synthesis of dermatan sulphate. If alternatively spliced variants of a protein possess GAG initiation sites, they may be referred to as ‘part-time’ proteoglycans [43]. GAG chains are additionally variably sulphated by sulpherotransferase enzymes. CSPGs will be

described in more detail due to their particular relevance to CNS plasticity and repair. CSPGs are a well-studied family of CNS ECM molecules. They are known to play an important role in preventing nerve growth and restricting plasticity following CNS injury and, as such, have been widely targeted in experimental strategies to promote repair in a number of experimental models [44–46]. Members of the CSPG family that are implicated in the response to CNS injury include the lecticans, NG2, phosphacan and the small leucine-rich proteoglycans decorin and biglycan. CS-GAG chains are sulphated at particular residues to form distinct motifs (see Figure 1B). In mammals GalNAc may be mono- or disulphated at C4 and/or C6 to produce chondroitin sulphate-A

learn more (CS-A; GlcA-4SGalNAc), chondroitin sulphate-C (CS-C; GlcA-6SGalNAc) and chondroitin sulphate-E (CS-E; GlcA-4S,6SGalNAc) or disulphated at C2 of GlcA and C6 of GalNAc to produce chondroitin sulphate-D (CS-D; GlcA-2S, 6SGalNAc). Chondroitn sulphate-B (CS-B) is dermatan sulphate [47,48]. Sulphation motifs bestow distinct interactive properties upon CSPGs and within PNNs, for example CS-E is specifically thought to provide an attachment site for the guidance cue semaphorin 3A [49,50]. The lecticans Myosin (also known as hyalectan) are the most abundant family of CSPGs within the CNS, comprising aggrecan, versican, neurocan and brevican. Lectican core proteins range in size from 145 kDa to over 300 kDa. They all possess an N-terminal G1 domain and C-terminal G3 domain (see Figure 1C). The G1 domain contains a HA-binding region and immunoglobulin-like

loop, interacting with HA and link protein to form stable ternary complexes in the ECM. The G3 domain comprises EGF repeats (both an EGF module and a calcium-binding EGF module), a C-type lectin domain (CLD) and a complement binding protein-like motif. The CLD has conserved expression across all lecticans and is involved in mediating interactions with other matrix components. This includes ligands with multimeric affinity to CLD such as tenascins, thus thought to enable assembly of cross-linked matrices [51]. Affinity of such interactions may also be regulated by alternative splicing of other G3 domains [52]. Aggrecan additionally includes a G2 domain which is of similar composition to the tandem repeats within G1, but not thought to impart additional interaction with HA [53,54].