title: Activation of survival pathways in the degenerating retina of rd10 mice.
abstract: Blinding diseases of the retina are frequently characterized by loss of photoreceptor cells. The retinal degeneration 10 (rd10) mouse expresses a mutant form of rod phosphodiesterase leading to autosomal recessive photoreceptor degeneration. In contrast to rd1, rd10 mice have remaining rod function mimicking more closely most forms of human Retinitis Pigmentosa. Here we use morphology, biochemistry, retinal whole mounts, real-time PCR, Western blotting and immunofluorescence to compile a comprehensive report on progression of retinal degeneration in the rd10 retina up to one year of age. We show that retinal development, morphology, gene expression pattern and retinal vasculature was normal until postnatal day 15. Thereafter, a bi-phasic pattern of rod cell death emerged with a first rapid phase peaking around 3 weeks of age followed by a slower second phase. Death of cone cells followed with a delay and vessel dropout was prominent in the retinal periphery of 6 months old rd10 mice. At one year of age, RPE atrophy was evident. The degenerating retina rapidly induced expression of transcriptional regulators Atf3 and Cebpd. Induction of Atf3 was transient and lasted only for several days at the beginning of degeneration whereas levels of Cebpd remained elevated throughout the period of photoreceptor loss. Several protective genes such as Lif, Edn2 and Fgf2 which are implicated in a potent endogenous survival pathway, and Mt1 and Mt2 were strongly upregulated in the rd10 retina. In addition, increased expression of Casp1 and Il1b suggested an inflammatory response.
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Zurich, Switzerland.
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.forename: Hedwig
authors.initials: H
authors.lastname: Wariwoda
authors.forename: Cornelia
authors.initials: C
authors.lastname: Imsand
authors.forename: Philipp
authors.initials: P
authors.lastname: Huber
authors.forename: Severin R
authors.initials: SR
authors.lastname: Heynen
authors.forename: Andrea
authors.initials: A
authors.lastname: Gubler
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001284:Atrophy; D015153:Blotting, Western; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D019333:Endothelin-2 / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D053605:Leukemia Inhibitory Factor / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C497253:Cebpd protein, mouse; D019333:Endothelin-2; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D016222:Fibroblast Growth Factor 2; D051743:CCAAT-Enhancer-Binding Protein-delta