S1P1 deletion in oligodendroglial lineage cells: Effect on differentiation and myelination.

Abstract

Sphingosine 1-phosphate (S1P) receptors are G protein-coupled receptors expressed by many cell types, including cells of oligodendrocyte (OLG) lineage. We had previously shown that targeted deletion of S1P1 in OLG lineage cells did not result in obvious clinical phenotype or altered number of OLGs at 3 months, but there were subtle abnormalities in myelin. In this study, we examined the role of S1P1 in developmental myelination and cell survival, focusing on age 3 weeks. We found that S1P1 deficiency led to delayed differentiation of OLG progenitors (OPCs) into OLGs that is independent of p38 phosphorylation. This was accompanied by decreased levels of myelin basic protein (MBP) but not of myelin-OLG glycoprotein (MOG), and slight decrease in myelin thickness in the corpus callosum of S1P1 conditional knockout (CKO) mice. S1P1 -deficient OLGs exhibited slower process extension, which was associated with attenuated phosphorylation of extracellular signal regulated kinases (ERKs) and p21-activated kinases (PAKs), and with upregulation of tropomodulin1. Basal levels of pAkt were not affected, though expectedly, no response to a selective S1P1 agonist SEW2871 was observed. S1P1 -deficient OLGs did not exhibit increased cell death in response to cuprizone, tumor necrosis factor-α, or deprivation of nutrients and growth factors. We conclude that S1P1 signaling regulates OLG development, morphological maturation and early myelination.