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N. P. Rotstein, C. E. Abrahan, L. E. Politi; Sphingosine-1-Phosphate Has a Key Role in the Crosstalk and Development of Retina Glial and Neuronal Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4307.
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© ARVO (1962-2015); The Authors (2016-present)
We have shown that Müller glial cells in coculture with retinal neurons preserve the proliferative potential of neuronal progenitors and protect neurons from oxidative stress, which in turn enhances glial proliferation. We have also identified the sphingolipid sphingosine-1-phosphate (S1P) as a crucial mediator in proliferation, survival and differentiation of photoreceptors. We have now investigated the roles played by S1P in neuroglial development.
Pure glial cultures and neuroglial cocultures prepared from rat retinas were treated with or without S1P. The effect of S1P on proliferation was evaluated by Br-deoxyuridine (BrdU) or [3H]thymidine uptake, and on neuronal migration and axonal growth and orientation by fluorescence and confocal microscopy, after staining cells with rhodamine-phalloidin and acetylated tubulin. Cocultures were treated with BML-241, a S1P receptor 3 (S1P3) antagonist or with a sphingosine kinase 1 (SphK1) inhibitor to inhibit S1P synthesis, and oxidative stress was then induced with the oxidant paraquat (PQ). Apoptosis was then determined by TUNEL labeling.
Addition of S1P increased [3H]thymidine and BrdU uptake in pure glial cultures and augmented BrdU uptake in neuroblasts in coculture. Inhibiting S1P synthesis or adding BML-241 before treating neuroglial cocultures with PQ blocked glial protection from oxidative stress-induced apoptosis in photoreceptors. S1P addition also regulated neuronal differentiation and organization in neuroglial cocultures. S1P promoted the aggregation and rearrangement of neurons in coculture, leading to the formation of conspicuous round aggregates mainly comprised of neurons; thick bundles of axons connected these aggregates, forming an extensive network that was absent in controls. Concurrently, S1P increased the expression of N-CAM, a cell adhesion molecule.
Our results suggest that S1P promotes proliferation of glial cells. S1P might also be among the key factors released by glial cells to prevent neuronal apoptosis, stimulate neuroblast proliferation and participate in neuronal migration and axonal outgrowth and orientation.
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