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The Journal of Neuroscience, February 9, 2005, 25(6):1459-1469; doi:10.1523/JNEUROSCI.4645-04.2005

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Cellular/Molecular
Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

C. Jaillard,1 * S. Harrison,2 * B. Stankoff,1 M. S. Aigrot,1 A. R. Calver,2 G. Duddy,2 F. S. Walsh,3 M. N. Pangalos,4 N. Arimura,5 K. Kaibuchi,5 B. Zalc,1 and C. Lubetzki1

1Biologie des Interactions Neurones/Glie, Institut National de la Santé et de la Recherche Médicale and Université Pierre et Marie Curie, Unité Mixte de Recherche 711, Institut Fédératif de Recherche des Neurosciences, Hôpital de la Salpêtrière, F-75651 Paris, France, 2GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom, 3Wyeth Research Discovery, Collegeville, Pennsylvania 19426, 4Wyeth Research, Neuroscience Discovery, Princeton, New Jersey 08852, and 5Department of Cell Pharmacology, Nagoya University Graduate School of Medicine Tsurumai, Showa, Nagoya 466-8550, Japan

Endothelial differentiation gene (Edg) proteins are G-protein-coupled receptors activated by lysophospholipid mediators: sphingosine-1-phosphate (S1P) or lysophosphatidic acid. We show that in the CNS, expression of Edg8/S1P5, a high-affinity S1P receptor, is restricted to oligodendrocytes and expressed throughout development from the immature stages to the mature myelin-forming cell. S1P activation of Edg8/S1P5 on O4-positive pre-oligodendrocytes induced process retraction via a Rho kinase/collapsin response-mediated protein signaling pathway, whereas no retraction was elicited by S1P on these cells derived from Edg8/S1P5-deficient mice. Edg8/S1P5-mediated process retraction was restricted to immature cells and was no longer observed at later developmental stages. In contrast, S1P activation promoted the survival of mature oligodendrocytes but not of pre-oligodendrocytes. The S1P-induced survival of mature oligodendrocytes was mediated through a pertussis toxin-sensitive, Akt-dependent pathway. Our data demonstrate that Edg8/S1P5 activation on oligodendroglial cells modulates two distinct functional pathways mediating either process retraction or cell survival and that these effects depend on the developmental stage of the cell.

Key words: oligodendrocytes; LPA receptors; S1P receptors; retraction; survival; myelin

Received July 30, 2004; accepted December 3, 2004.




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