Sulphation patterns orchestrate the function of chondroitin sulphate proteoglycans (CSPGs) in the brain extracellular matrix

Orateur : Jessica KWOK (John van Geest Centre for Brain Repair, University of Cambridge, United Kingdom)

The importance of chondroitin sulphate proteoglycans (CSPGs) in the nervous system has become evident in the last two decades when strong up-regulation of CSPGs was reported around the lesioned area after injury in the central nervous system (CNS). The functions of CSPGs have since evolved from being a pure structural component in the brain matrix, to a strong inhibitor in regeneration and more recently, as a plasticity regulator during development and regeneration in the CNS. We have previously shown that aggregation of CSPGs, hyaluronan, link proteins and tenascin R into a structure called perineuronal nets (PNNs) determine the degree of plasticity during CNS development and after injury. Our recent studies demonstrate that the various sulphation forms of chondroitin sulphates (CSs) modulate the functions of CSPGs in the brain matrix. With the use of chondroitin 6-sulphotransferase-1 knockout mice in which chondroitin 6-sulphate (C6S) production is diminished, we demonstrated that the depletion of C6S leads to a reduction in nerve regeneration after CNS injury when compared to the wild-type controls. This suggests that C6S is crucial for basal regeneration in the CNS. In early CNS development, the balance of C6S and C4S controls the development of the vestibular system - while C6S leads to an enhancement in axonal growth, C4S arrested the growth. In the PNNs, we demonstrate that the enrichment of CS-E (i.e. C4,6-S) in the CSPGs facilitate the binding of inhibitory semaphorin 3A (Sema3A), which in turn imposes further inhibition of PNNs on neuronal growth. These results demonstrate that fine-tuning the sulphation patterns of CSs in the milieu of neurons may facilitate neuronal regeneration after injury.

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