The Role of Chondroitin Sulfate Proteoglycans in Nervous System Development

Abstract

The orderly development of the nervous system is characterized by phases of cell proliferation and differentiation, neural migration, axonal outgrowth and synapse formation, and stabilization. Each of these processes is a result of the modulation of genetic programs by extracellular cues. In particular, chondroitin sulfate proteoglycans (CSPGs) have been found to be involved in almost every aspect of this well-orchestrated yet delicate process. The evidence of their involvement is complex, often contradictory, and lacking in mechanistic clarity; however, it remains obvious that CSPGs are key cogs in building a functional brain. This review focuses on current knowledge of the role of CSPGs in each of the major stages of neural development with emphasis on areas requiring further investigation:

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…This contrasts with multiple CS/HS-binding chemoattractive factors which display variable roles during the complex interplay between attractive and repulsive cellular effects in the guidance of sensory axons to specific target sites [ 89 ]. CS-PGs also have important roles to play in the formation of synapses in PNNs and roles in neuronal plasticity, and the stabilisation and myelination of axons which maintain optimal electroconductive properties of neural networks [ 5 ].…”

“…These convey PGs with a range of cell-directive properties through interactions with guidance neuroregulatory, adhesive and structural glycoproteins and with cellular receptors, growth factors, chemokines and cytokines. Thus, PGs influence diverse cellular processes such as proliferation, differentiation, cellular migration and ECM assembly/remodelling in development and in tissue repair [ 4 , 5 , 6 , 7 ]. CNS/PNS astrocytes, neurons and glial cells synthesize PGs decorated with chondroitin sulphate (CS), keratan sulphate (KS), dermatan sulphate (DS), heparan sulphate (HS) and the human natural killer-1 (HNK-1) trisaccharide (SO 4 -3GlcAβ1-3Galβ1-4GlcNAc) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

“…CNS/PNS astrocytes, neurons and glial cells synthesize PGs decorated with chondroitin sulphate (CS), keratan sulphate (KS), dermatan sulphate (DS), heparan sulphate (HS) and the human natural killer-1 (HNK-1) trisaccharide (SO 4 -3GlcAβ1-3Galβ1-4GlcNAc) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Decoration of neural PG core proteins with these GAGs equips them with the capability of guiding embryonic nerve development and the formation of neural networks, as well as the development of the neural microvasculature [ 4 , 5 , 6 ]. Members of the lectican PG family interact with hyaluronan (HA) and tenascin-R to form specialized macromolecular ECM structures known as perineuronal nets (PNNs).…”

Hyalectanase Activities by the ADAMTS Metalloproteases

“…Functional relevance of PGs in the ECM assembly is also evident when different pathological processes have been related with alterations affecting their physiological role [1,2]. For instance, different studies point out that the interaction of PGs with molecular partners of the ECM is essential for the correct maintenance of neuronal functions and the development of the nervous system [3][4][5][6]. Consequently, PGs have been associated with the development of different neurodegenerative disorders including those resulting in cognitive impairment as occurs in Alzheimer's disease [7].…”

Exciting New Developments and Emerging Themes in Glycosaminoglycan Research

“…CSPGs are further explored by Mencio et al 11 who discuss and update our understanding of their role in neural development. In a recurring theme across these reviews, the authors highlight how specific sulfation patterns within GAGs can be associated with both inhibition and promotion of an effect, here neural regeneration after injury, with the outcome being time- and position-dependent.…”