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The Journal of Neuroscience, May 15, 2003, 23(10):4208-4218

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The Growth Arrest-Specific Gene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Sai Latha Shankar,¹ Kathleen O'Guin,¹ Michael Cammer,² F. Arthur McMorris,³ Trevor N. Stitt,⁴ Ross S. Basch,⁵ Brian Varnum,⁶ and Bridget Shafit-Zagardo¹

¹Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, ²Department of Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, New York 10461, ³The Wistar Institute, Philadelphia, Pennsylvania 19104, ⁴Regeneron Pharmaceuticals, Tarrytown, New York 10591, ⁵Department of Pathology, New York University School of Medicine, New York, New York 10016, and ⁶Amgen Corporation, Thousand Oaks, California 91320

Microarray analysis revealed that transcripts for the Axl and Mer receptor tyrosine kinases are expressed at high levels in O4⁺-immunopanned oligodendrocytes isolated from second trimester human fetal spinal cord. In humans the sole known ligand for the Axl/Rse/Mer kinases is growth arrest-specific gene 6 (Gas6), which in the CNS is secreted by neurons and endothelial cells. We hypothesized that Gas6 is a survival factor for oligodendrocytes and receptor activation signals downstream to the phosphatidylinositol 3 (PI3)-kinase/Akt pathway to increase cell survival in the absence of cell proliferation. To test this hypothesis, we grew enriched human oligodendrocytes for 6 d on a monolayer of NIH3T3 cells stably expressing Gas6. CNP⁺ oligodendrocytes on Gas6-secreting 3T3 cells had more primary processes and arborizations than those plated solely on 3T3 cells. Also, a twofold increase in CNP⁺ and MBP⁺ oligodendrocytes was observed when they were plated on the Gas6-secreting cells. The effect was abolished in the presence of Axl-Fc but remained unchanged in the presence of the irrelevant receptor fusion molecule TrkA-Fc. A significant decrease in CNP⁺/TUNEL⁺ oligodendrocytes was observed when recombinant human Gas6 (rhGas6) was administered to oligodendrocytes plated on poly-L-lysine, supporting a role for Gas6 signaling in oligodendrocyte survival during a period of active myelination in human fetal spinal cord development. PI3-kinase inhibitors blocked the anti-apoptotic effect of rhGas6, whereas a MEK/ERK inhibitor had no effect. Thus Gas6 sustains human fetal oligodendrocyte viability by receptor activation and downstream signaling via the PI3-kinase/Akt pathway.

Key words: Gas6; oligodendrocytes; human spinal cord; apoptosis; tyrosine kinase receptors; Axl/Rse/Mer

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Received Nov. 22, 2002; revised Feb. 26, 2003; accepted Feb. 28, 2003.

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