The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway.
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.
Shankar
Sai Latha
SL
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
O'Guin
Kathleen
K
Cammer
Michael
M
McMorris
F Arthur
FA
Stitt
Trevor N
TN
Basch
Ross S
RS
Varnum
Brian
B
Shafit-Zagardo
Bridget
B
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D009836:Oligodendroglia / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D000099255:Growth Arrest-Specific Protein 6; C494918:AKT1 protein, human