Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells.
Sphingosine-1-phosphate (S1P) is a lipid mediator that exerts multiple cellular functions through activation of G-protein-coupled receptors. Although the role of S1P on angiogenesis is well established, its role in neurogenesis is unknown. We examined the effects of S1P on G-protein activation in brain sections of rat embryo and on neural progenitor cells in culture. Intense S1P-stimulated [35S]GTPgammaS labeling was observed as early as E15 in the neuroepithelium and differentiating fields throughout the brain, suggesting that functional S1P receptors are expressed in brain areas with active neurogenesis. mRNA transcripts for several S1P receptor subtypes (S1P1, S1P2, S1P3 and S1P5) were expressed in neural progenitor cells prepared from embryonic rat hippocampus. S1P induced phosphorylation of extracellular signal-regulated kinase (ERK) and proliferation of neural progenitor cells as determined by BrdU incorporation in a pertussis toxin-sensitive manner. These effects were prevented by the ERK signaling inhibitor U0126. S1P augmented telomerase activity in neural progenitor cells with similar potency as that of FGF-2. Furthermore, S1P induced cell-cell aggregation. This morphological change was transient and prevented by Y-27632, an inhibitor of Rho-associated kinase. These results suggest that S1P plays a pleiotropic role in neurogenesis via pathways involving S1P receptors, MAP kinases and Rho kinase.
Harada
Jun
J
Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Foley
Melissa
M
Moskowitz
Michael A
MA
Waeber
Christian
C
D000818:Animals; D001345:Autoradiography / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004277:DNA, Single-Stranded / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000196:embryology; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008246:Lysophospholipids; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins; D064231:Nestin; D009474:Neurons / Q000187:drug effects*; D019081:O Antigens / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D013460:Sulfur Isotopes; D019098:Telomerase / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
C400152:DNA enzyme ED5; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D019081:O Antigens; C430944:O4 antigen, Stenotrophomonas; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D013460:Sulfur Isotopes; D014404:Tubulin; C462941:beta3 tubulin, mouse; D016222:Fibroblast Growth Factor 2; C060506:sphingosine 1-phosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020928:Mitogen-Activated Protein Kinases; D019098:Telomerase; D001973:Bromodeoxyuridine; D013110:Sphingosine