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S1P1 deletion in oligodendroglial lineage cells: Effect on differentiation and myelination
Danuta E Dukala1, Betty Soliven1
1Department of Neurology, the University of Chicago, Chicago, Illinois.
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.
Insights
Sphingosine 1-phosphate 1 (S1P1) receptor deficiency in oligodendrocytes delays their development and myelination. This impacts myelin basic protein levels and thickness, affecting oligodendrocyte maturation and early myelination processes.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Sphingosine 1-phosphate (S1P) receptors are crucial G protein-coupled receptors.
- Oligodendrocytes (OLGs) express S1P receptors and are vital for myelin sheath formation in the central nervous system.
- Previous studies indicated subtle myelin abnormalities upon S1P1 deletion in OLGs.
Purpose of the Study:
- To investigate the role of S1P1 in oligodendrocyte development and myelination during early life stages.
- To assess the impact of S1P1 deficiency on oligodendrocyte progenitor cell (OPC) differentiation and maturation.
- To determine the effect of S1P1 deficiency on oligodendrocyte survival under various stress conditions.
Main Methods:
- Utilized S1P1 conditional knockout (CKO) mouse models focusing on 3-week-old animals.
- Analyzed oligodendrocyte differentiation, myelin basic protein (MBP) and myelin-oligodendrocyte glycoprotein (MOG) levels, and corpus callosum myelin thickness.
- Assessed oligodendrocyte process extension, extracellular signal-regulated kinases (ERKs), p21-activated kinases (PAKs), and Akt phosphorylation.
- Evaluated oligodendrocyte survival following exposure to cuprizone, TNF-α, or nutrient deprivation.
Main Results:
- S1P1 deficiency resulted in delayed OPC differentiation into OLGs, independent of p38 phosphorylation.
- Decreased MBP levels and reduced myelin thickness were observed in the corpus callosum of S1P1 CKO mice.
- S1P1-deficient OLGs showed impaired process extension, linked to attenuated ERK and PAK phosphorylation and increased tropomodulin1.
- No increased cell death was observed in S1P1-deficient OLGs under various stress conditions.
Conclusions:
- S1P1 signaling is essential for normal oligodendrocyte development and morphological maturation.
- S1P1 plays a regulatory role in early myelination processes.
- S1P1 is not critical for oligodendrocyte survival under the tested stress conditions.
