CONICET | Buscador de Institutos y Recursos Humanos

SPHINGOSINE-1-PHOSPHATE PROMOTES THE PROLIFERATION AND DIFFERENTIATION OF RETINA PHOTORECEPTORS Gisela E. Miranda and Nora P. Rotstein. Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS), Bahía Blanca, Buenos Aires, Argentina. Objective: docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, prevents apoptosis and promotes differentiation of photoreceptors. DHA decreases the levels of ceramide to promote photoreceptor survival (IOVS 47:1658, 2006) suggesting that sphingolipids might mediate other effects of DHA on photoreceptors. We now investigated whether sphingosine-1-phophate (S1P) regulates proliferation and differentiation in photoreceptors. Methods: Pure rat retina neurons in culture were supplemented with or without DHA or GDNF and/or S1P. The cultures were also treated with an inhibitor of Sphingosine Kinase (SK) to block S1P synthesis, or with Brefeldin A (BFA) which collapses the Golgi into the ER. Photoreceptor differentiation was determined by evaluating the amount of apical processes and opsin and peripherin expression. Proliferation was evaluated counting mitotic figures and BrdU uptake. Results: photoreceptors in control cultures had few apical processes and opsin was distributed over the whole cell body and neurites. S1P or DHA enhanced the development of apical processes, increased opsin and peripherin expression and promoted their localization in apical processes. Inhibiting S1P synthesis blocked DHA-induced increase in photoreceptor differentiation and addition of S1P to these cultures restored photoreceptor differentiation. Treatment of DHA or S1P-supplemented cultures with Brefeldin A decreased the formation of apical processes, without affecting opsin or peripherin expression. Though S1P and DHA had similar effects on differentiation, they did not share their effect on proliferation. DHA induces the exit of photoreceptor progenitors from the cell cycle while glial derived neurotrophic factor (GDNF) promotes their proliferation. S1P treatment enhanced proliferation of photoreceptor progenitors, while inhibition of S1P synthesis blocked GDNF effect on proliferation. Conclusions: These results suggest that S1P is a key mediator in photoreceptor proliferation and differentiation; GDNF and DHA might enhance its synthesis at different times in development to regulate the former the amount of photoreceptors and the latter their differentiation.

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