Cell cycle regulation in retinal progenitors by glial derived neurotrophic factor and docosahexaenoic acid”.

M. FERNANDA INSUA; ANDRÉS GARELLI; NORA P. ROTSTEIN; LORENA GERMAN; ANDRÉS ARIAS; LUIS E. POLITI

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE

Assoc Research Vision Ophthalmology Inc

Año: 2003 vol. 44 p. 2235 - 2244

0146-0404

PURPOSE. We have recently shown that glial derived neurotrophic factor (GDNF) and docosahexaenoic acid (DHA) promote the survival and differentiation of retina photoreceptors. We now investigated whether these molecules could participate in cell cycle regulation in retinal progenitors in vitro. METHODS. Developmental changes in the expression of cell cycle markers, of stem cell marker nestin and of mature neurons were analyzed in neuroblasts obtained from one day-old rat retinas. The effects of GDNF and DHA on those changes were then determined. RESULTS. Expression of nestin, found in over one third of neuroblasts at day 1, rapidly decreased during development, with most of neuroblasts acquiring the photoreceptor phenotype. GDNF increased the percentage of photoreceptor progenitors expressing nestin while 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 two days in vitro. GDNF stimulated the cell cycle, increasing the number of dividing cells and generating more photoreceptor progenitors, while DHA induced cell cycle exit and photoreceptor differentiation. Analysis of cyclin-Cdk inhibitor p27Kip1 expression confirmed these results. CONCLUSIONS. GDNF and DHA acted as molecular cues, counterbalancing the decision of photoreceptors to remain in or exit the cell cycle. These and previous data strongly suggest that both factors participate in determining photoreceptor number in vitro, regulating cell cycle and survival at early and late stages of development, respectively. Hence, GDNF and DHA might coordinately control the histogenesis of photoreceptors in the retina by modulating both neurogenesis and apoptosis.