Sphingosine-1-phosphatepromotes the proliferation and differentiation of retina photoreceptors

MIRANDA, GISELA; ROTSTEIN, NORA

Los Cocos, Córdoba, Argentina

Workshop; Workshop: "From Light perception to Vision. Seeking for Retinal Function and Evolution"; 2007

Facultad de ciencias quimicas-Universidad Nacional de Cordoba

We have previously established that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, prevents apoptosis and promotes differentiation of photoreceptors. Our recent finding that DHA decreases the levels of ceramide, a sphingolipid mediator in oxidative stress-induced apoptosis of photoreceptors, to promote survival suggests that sphingolipids might regulate other effects of DHA on photoreceptors. We have now investigated whether sphingosine-1-phophate (S1P), a sphingolipid known to promote survival and proliferation in several cell types, regulates proliferation and differentiation in photoreceptors. Supplementation with 1 mM S1P or with 6.7 mM DHA of rat neuronal cultures at day 1 enhanced the development of apical processes, increased expression of opsin and to a lower extent that of peripherin, an outer segment marker, and promoted their localization in apical processes.  Inhibiting S1P synthesis blocked DHA-induced increase in 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 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 also enhanced proliferation, increasing the amount of mitotic figures and promoting BrdU uptake in photoreceptor progenitors. 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 amount and differentiation of photoreceptors.