Cell cycle regulation in retinal progenitors by glia-derived neurotrophic factor and docosahexaenoic acid

Abstract

PURPOSE. A recent study has shown that glia-derived neurotrophic factor (GDNF) and docosahexaenoic acid (DHA) promote the survival and differentiation of retina photoreceptors. The current study was undertaken to investigate whether these molecules participate in cell cycle regulation in retinal progenitors in vitro. METHODS. Developmental changes in the expression of the stem cell marker nestin and of cell cycle and differentiated neuron markers were analyzed in neuroblasts obtained from 1-day-old rat retinas. The effects of GDNF and DHA on those changes were then determined. RESULTS. Expression of nestin, found in more than one third of neuroblasts at day 1, rapidly decreased during development, with most neuroblasts acquiring the photoreceptor phenotype. GDNF increased the percentage of photoreceptor progenitors expressing nestin, whereas DHA reduced it, simultaneously enhancing photoreceptor differentiation. Several markers of cell cycle progression indicated that photoreceptor progenitors maintained an active cell cycle during the first 2 days in vitro. GDNF stimulated the cell cycle, increasing the number of dividing cells and generating more photoreceptor progenitors, whereas DHA induced cell cycle exit and photoreceptor differentiation. Analysis of the expression of the cyclin-Cdk inhibitor p27Kip1 confirmed these results. CONCLUSIONS. GDNF and DHA acted as molecular cues, counterbalancing the decision of photoreceptors to remain in or exit the cell cycle. The results strongly suggest that both factors participate in determining the number of photoreceptors in vitro, regulating the cell cycle and survival at early and late stages of development, respectively. Hence, GDNF and DHA may coordinately control the histogenesis of photoreceptors in the retina by modulating both neurogenesis and apoptosis.