The role of the NG2 proteoglycan in OPC and CNS network function

• NG2 is a type-1 membrane protein specifically expressed by OPC in the CNS.
• NG2 is cleaved by α- and γ-secretase in response to neuronal activity.
• Cleavage results in ectodomain, CTF and ICD NG2 fragments.
• Each fragment has defined physiological roles in the CNS.
• The neuronal network is modulated by the LNS domains of the released ectodomain.

In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS.This article is part of a Special Issue entitled SI:NG2-glia(Invited only).