CONICET | Buscador de Institutos y Recursos Humanos

SPHINGOSINE-1-PHOSPHATE: A KEY MEDIATOR IN THE DEVELOPMENT 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. Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, and Glial Derived Neurotrofic Factor (GDNF) promote survival and differentiation, and proliferation of photoreceptors, respectively. 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), a sphingolipid known to promote survival and proliferation in several cell types, regulates proliferation and differentiation in rat retina photoreceptors in culture. Supplementation with DHA or S1P enhanced the development of apical processes, increased opsin and peripherin expression and promoted their localization in these processes. While inhibition of S1P synthesis, using an inhibitor of Sphingosine Kinase (SK), blocked DHA-induced increase in photoreceptor differentiation, addition of S1P to these cultures restored photoreceptor differentiation. Treatment of DHA or S1P-supplemented cultures with Brefeldin A, which collapses the Golgi into the ER, decreased the formation of apical processes, without affecting opsin or peripherin expression. We have previously shown that GDNF promoted the proliferation of photoreceptor progenitors. S1P also enhanced this proliferation and, interestingly, inhibition of its synthesis blocked GDNF effect on proliferation. When the effect of DHA and GDNF on SK expression was investigated, both trophic factors were found to increase the levels of SK in photoreceptors. These data suggest that at different times during development GDNF and DHA might enhance S1P synthesis through an increase in SK levels, to regulate the amount of photoreceptors and their differentiation, respectively. Conversely, inhibiting S1P synthesis blocks both processes. Hence, our results support the proposal of S1P as a key mediator in photoreceptor proliferation and differentiation.

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