title: DNA Damage Response in Proliferating Müller Glia in the Mammalian Retina.
abstract: OBJECTIVE
  Müller glia, the principal glial cell type in the retina, have the potential to proliferate and regenerate neurons after retinal damage. However, unlike the situation in fish and birds, this capacity of Müller glia is extremely limited in mammals. To gain new insights into the mechanisms that hamper retinal regeneration in mammals, we examined the cell cycle progression and DNA damage response in Müller glia after retinal damage.
  
  
  METHODS
  Expression of cell cycle-related proteins and DNA damage response were analyzed in adult rat and mouse retinas after N-methyl-N-nitrosourea (MNU)- or N-methyl-D-aspartate (NMDA)-induced retinal damage. Zebrafish and postnatal rat retinas were also investigated for comparison. Analysis was conducted by using immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  In the rat retina, most Müller glia reentered the cell cycle after MNU-induced photoreceptor damage while no proliferative response was observed in the mouse model. Cell cycle reentry of rat Müller glia was accompanied by DNA damage response including the phosphorylation of the histone variant H2AX and upregulation of p53 and p21. The DNA damage response was also observed in rat Müller glia after NMDA-induced loss of inner retinal neurons, but not in zebrafish Müller glia or rat retinal progenitor cells.
  
  
  CONCLUSIONS
  Our findings suggest that the DNA damage response induced by unscheduled cell cycle reentry may be one of the mechanisms that limit the proliferative and regenerative capacity of Müller glia in the mammalian retina.
authors.affiliation: Department of Anatomy School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Nomura-Komoike
authors.affiliation: Department of Anatomy School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Saitoh
authors.affiliation: Department of Hygiene and Public Health I, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Komoike
authors.affiliation: Department of Anatomy School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fujieda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000235:genetics; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055351:Retinal Neurons / Q000378:metabolism / Q000473:pathology*
chemical_list: D019938:Cyclin D1; D012313:RNA; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4