Regulation of Oligodendrogenesis by Sulfatides and PDGFrα

Sulfatides, a significant constituent of myelin, regulate oligodendrogenesis by unknown mechanism. Therefore, we hypothesized that sulfatides affect very early events during gliogenesis regulating the differentiation of multipotential neural progenitors (NPs) and oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). In this study we show that an increased content of endogenous and exogenous sulfatides negatively affects the differentiation capacity of NPs, oligodendrogenesis, and the activity of PDGFrα pathway, a signaling critical in oligodendrogenesis. Sulfatide accumulation in ASA-/- animals, deficient in arylsulfatase A (ASA), an enzyme responsible for the degradation of sulfatides, is associated with a delay in myelination. In vitro studies of ASA-/- NPs show a significantly reduced formation of OLs associated with a decreased level of PDGFrα. There is preferential accumulation of sulfatides in lipid rafts (LRs) and exacerbated exosomal shedding of the PDGFrα. Rescue experiments with ASA normalized the receptor level and the production of OLs. We show that the exosomal shedding of PDGFrα occurs during early postnatal development concurrent with myelination, possibly to tether the sensitivity of OLs to mitogens during myelination. In addition, we show that an increased level of exogenous sulfatides and individual isoforms (C16:0, C18:0, C24:0 and C24:1), negatively affect the gliogenic capacity of ASA+/+ NPs, reducing the formation of O4+ OPCs and O1+ OLs. Studies performed in central glial 4 cells (CG4) exposed for 24 h. to sulfatides show normal levels of PDGFrα. However, sulfatides led to the movement of receptor to the lipid rafts compartment. Functional analysis of PDGFrα after exposure to sulfatides shows a reduction in the phosphorylation of receptor at Tyr720, a residue responsible for activation of MAPKs. Sulfatides led to the reduction in a phosphorylation of ERK2 at Tyr204, a site regulating the transcriptional activation of genes important in proliferation and survival in oligodendrocytes. These findings provide the first molecular evidence that sulfatides may regulate oligodendrogenesis by differential modifications of membrane-bound signals such as that mediated by PDGFrα.