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.

Keywords: axon guidance; extracellular matrix; glycosaminoglycans; neural migration; neurogenesis; proteoglycans; synapse formation.

Figure 1.

Common methods for GAG modification and CSPG identification. (A) A representative CSPG that contains some DS residues and varied sulfation patterns that can be identified using antibodies directed against epitopes in the GAG chain and core protein. (B) After complete enzymatic digestion by ChABC, GAG chains are reduced to short “stubs” that are recognized by antibodies directed against the core protein or remaining stub. (C) Xyloside treatment results in the formation of GAG chains that are not tethered to a core protein and CSPGs that lack GAG chains or have shortened GAG chains. Core protein antibodies are still effective. (D) Sodium chlorate treatment leads to GAG chains that lack sulfation. Core protein antibodies can still be used in identification, as can anti-CS-O antibodies. Abbreviations: GAG, glycosaminoglycan; CSPG, chondroitin sulfate proteoglycans; DS, dermatan sulfate; CS: chondroitin sulfate.

Figure 2.

CSPGs affects proliferation and differentiation of neural stem cells. Adding CSPG along with FGF2 causes an increase in proliferation of neuronal stem cells that differentiate into a higher percentage of neurons vs. glia. Removal of CS using ChABC results in reduced proliferation and a higher percentage of glia vs neurons. After Ida et al. and Sirko et al. Abbreviation: CSPG, chondroitin sulfate proteoglycans; FGF, fibroblast growth factor.

Figure 3.

CSPGs help direct migration of neural crest cells. (A) In normal migration, cells migrate from the neural tube over the anterior portion of the sclerotome, seen in green, while avoiding the posterior, seen in red, which contains high levels of versican. (B) The removal of CS chains using ChABC leads to cells migrating in both the anterior and posterior sclerotome. (C) The addition of exogenous CSPG blocks neural crest cell migration. After Oakley and Tosney, Landolt et al., Moro Balbas et al., Perissinotto et al. Abbreviation: CSPG, chondroitin sulfate proteoglycans.

Figure 4.

CSPGs serves as guidance cues for optic tract axons during development. (A) In normal development, the optic tract avoids the CSPG-rich areas of the telencephalon and the diencephalon and grows into the optic tectum. (B) When exogenous CS is added, retinal axon targeting is disrupted, and axons grow across the entire area. (C) When CS is removed using ChABC, the optic tract still terminates in the tectum, however it deviates slightly toward the telencephalon. After Walz et al., Tuttle et al., Ichijo and Kawabata. Abbreviation: CSPG, chondroitin sulfate proteoglycans; ot, optic tract; Tel, telencephalon; Di, diencephalon.

Figure 5.

Increased chondroitin sulfate leads to reduced synaptic plasticity. Synapse formation and dendritic spines are sensitive to the presence of CSPGs. Enzymatic degradation of chondroitin sulfate by ChABC leads fluctuations in dendritic spine size and number which facilitates increased synapse plasticity. With development, there is an increased presence of CSPGs in perineuronal nets, which restrict synapse plasticity. Abbreviation: CSPG, chondroitin sulfate proteoglycans.