CS-4,6 is differentially upregulated in glial scar and is a potent inhibitor of neurite extension

Department of Cell Biology, Emory University, Atlanta, Georgia, United States
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 09/2005; 29(4):545-58. DOI: 10.1016/j.mcn.2005.04.006
Source: PubMed


The precise contribution of different CS-GAGs to CSPG-mediated inhibition of axonal growth after CNS injury is unknown. Quantification of the CS-GAGs in uninjured and injured brain (scar tissue) using fluorophore-assisted carbohydrate electrophoresis (FACE) demonstrated that the dominant CS-GAG in the uninjured brain is CS-4 whereas, in glial scar, CS-2, CS-6, and CS-4,6 were over-expressed. To determine if the pattern of sulfation influenced neurite extension, we compared the effects of CS-GAGs with dominant CS-4, CS-6, or CS-4,6 sulfation to intact CSPG (aggrecan), chondroitin (CS-0), and hyaluronan on chick DRG neurite outgrowth. We report that CS-4,6 GAG, one of the upregulated CS-GAGs in astroglial scar, is potently inhibitory and is comparable to intact aggrecan, a CSPG with known inhibitory properties. Thus, a specific CS-GAG that is differentially over-expressed in astroglial scar is a potent inhibitor of neurite extension. These results may influence the design of more specific strategies to enhance CNS regeneration after injury.

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    • "While the contribution of CSPGs to the inhibitory nature of the glial scar has been known for many years (see review by Silver and Miller, 2004), mechanistic explanation as to how CSPGs inhibit advancing growth cones was lacking—until recently. For years it was posited that CSPGs exert inhibition through relatively nonspecific mechanisms such as substrate occlusion (McKeon et al., 1995), or presentation of a negatively charged boundary that repels growing axons (Gilbert et al., 2005). This view has changed considerably with the discovery of several receptors that directly bind sulfated glycosaminoglycan moieties (Dickendesher et al., 2012; Fisher et al., 2011; Shen et al., 2009) (Fig. 5H). "
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    • "After lesions, CSPGs are upregulated several-fold, peaking at between 10 to 14 days post-lesion [2] . Together with activated glial cells, the CSPGs form a dense layer of glial scar inhibitory to axon growth, and much of this inhibition is due to the activity of the glycosaminoglycan (GAG) chains [3] . in addition, CSPGs are major components of the perineuronal nets (PNNs), which are dense ECM structures that form around many neuronal cell bodies and dendrites late in development [4] [5] . in the spinal cord, PNNs surround ~30% of motoneurons in the ventral horn, 50% of large interneurons in the intermediate grey, and 20% of neurons in the dorsal horn [4] , while in the brain they are particularly associated with inhibitory GABAergic interneurons. The PNNs in the visual cortex form in the second week of postnatal development, which coincides with closure of the critical period for visual functions [6] . "
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    • "Like C4S, C6S increases in the spinal cord after injury [20] and inhibits axonal regeneration in cortical brain lesions [21]. However, other studies reported that C4S is neither up-regulated after cortical injury nor inhibitory to dorsal root ganglion axon outgrowth in vitro, and suggested C4, 6S (CS-E) is a potentially inhibitory molecule [26]. C6S binding peptides, obtained from a peptide phage display library, can block C6S and enhance cortical neurite outgrowth [22], [23], suggesting an inhibitory role of C6S for cortical neurons. "
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