title: Retinoic acid promotes apoptosis and differentiation in photoreceptors by activating the P38 MAP kinase pathway.
abstract: OBJECTIVE
  Retinoic acid (RA) has a critical role during development of the retina. We investigated RA effects on photoreceptor apoptosis and differentiation, and the intracellular pathways involved.
  
  
  METHODS
  Rat retinal neuronal cultures were supplemented with RA with or without docosahexaenoic acid (DHA), a photoreceptor survival factor, and photoreceptor apoptosis and differentiation were evaluated at different times of development. To investigate the intracellular pathways activated by RA, the levels of phosphorylated (P) ERK and P-p38 in cultures with or without RA, and the effect of pretreatment with SB203580, a p38 specific inhibitor, on apoptosis and differentiation were evaluated.
  
  
  RESULTS
  RA addition at day 0, when cells still were proliferating, selectively increased apoptosis in photoreceptors, whereas addition at day 2 no longer caused cell death. RA stimulated opsin and peripherin expression, and neurite outgrowth regardless of the time of development. Addition of RA at day 0, but not at day 2, rapidly increased P-p38 levels, but did not affect P-ERK levels. p38 inhibition completely prevented RA-induced apoptosis, and partially decreased differentiation. DHA prevented apoptosis and additively increased differentiation, without affecting RA activation of p38.
  
  
  CONCLUSIONS
  Our results show that RA activation of the p38 intracellular pathway was essential for its early induction of apoptosis and partially responsible for promoting differentiation. DHA prevention of this apoptosis suggests that RA effects during early development must be counterbalanced by survival factors to prevent photoreceptor death, in an interplay that might help to establish the final number of photoreceptors.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: De Genaro
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Simón
authors.forename: Nora P
authors.initials: NP
authors.lastname: Rotstein
authors.forename: Luis E
authors.initials: LE
authors.lastname: Politi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D055351:Retinal Neurons / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D004281:Docosahexaenoic Acids; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: apoptosis; photoreceptors; retinoid