Sugar-dependent modulation of neuronal development, regeneration, and plasticity by chondroitin sulfate proteoglycans

Abstract

Chondroitin sulfate proteoglycans (CSPGs) play important roles in the developing and mature nervous system, where they guide axons, maintain stable connections, restrict synaptic plasticity, and prevent axon regeneration following CNS injury. The chondroitin sulfate glycosaminoglycan (CS GAG) chains that decorate CSPGs are essential for their functions. Through these sugar chains, CSPGs are able to bind and regulate the activity of a diverse range of proteins. CSPGs have been found both to promote and inhibit neuronal growth. They can promote neurite outgrowth by binding to various growth factors such as midkine (MK), pleiotrophin (PTN), brain-derived neurotrophic factor (BDNF) and other neurotrophin family members. CSPGs can also inhibit neuronal growth and limit plasticity by interacting with transmembrane receptors such as protein tyrosine phosphatase σ (PTPσ), leukocyte common antigen-related (LAR) receptor protein tyrosine phosphatase, and the Nogo receptors 1 and 3 (NgR1 and NgR3). These CS-protein interactions depend on specific sulfation patterns within the CS GAG chains, and accordingly, particular CS sulfation motifs are upregulated during development, in the mature nervous system, and in response to CNS injury. Thus, spatiotemporal regulation of CS GAG biosynthesis may provide an important mechanism to control the functions of CSPGs and to modulate intracellular signaling pathways. Here, we will discuss these sulfation-dependent processes and highlight how the CS sugars on CSPGs contribute to neuronal growth, axon guidance, and plasticity in the nervous system.

Keywords: Axon guidance; Axon regeneration; CSPG; CSPG receptor; Chondroitin sulfate (CS); Glycosaminoglycans; Neuronal growth; Neuronal injury; Plasticity; Proteoglycan.

Figure 1

(A) Common sulfation motifs of chondroitin sulfate, which consists of the repeating disaccharide N-acetyl-D-galactosamine-β(1,3)-D-glucuronic acid. n = 20–100. CS-A and CS-C are monosulfated at the 4-O and 6-O positions of GalNAc, respectively. CS-D is sulfated at the 2-O position of GlcA and 6-O position of GalNAc. CS-E is sulfated at the 4-O and 6-O positions of GalNAc. (B) Biosynthesis of chondroitin sulfate. A core tetrasaccharide (xylose (Xyl)-galactose (Gal)-galactose (Gal)-glucuronic acid (GlcA)) is appended to serine residues of the core proteoglycan. Chain extension is performed by chondroitin sulfate synthase (CSS) and chondroitin polymerizing factor (ChPF). The polysaccharide chains are then elaborated through sulfation by C4ST to generate CS-A or C6ST to generate CS-C, followed by GalNAc4S-6ST or UST to form CS-E or CS-D, respectively.

Figure 2

Modulation of intracellular signaling pathways by chondroitin sulfate. (left) CS chains can localize soluble ligands such growth factors to the cell surface and facilitate interactions with their cognate receptors. For example, nerve growth factor (NGF) signaling and neurite outgrowth are enhanced when CS-E is presented on the cell surface. (right) Alternatively, CS chains can directly interact with transmembrane receptors such PTPσ, LAR, NgR1 and NgR3, and affect intracellular signaling. For example, CS interacts with lysine-rich IgG domains of PTPσ and inhibits neurite outgrowth.