Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy

Cell Cycle. 2015;14(22):3544-56. doi: 10.1080/15384101.2015.1080399.


Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events in AMD is poorly understood. Senescence-accelerated OXYS rats develop AMD-like retinopathy. The aim of this study was to explore the differences in retinal gene expression between OXYS and Wistar (control) rats at age 20 d and to identify the pathways of retinal cell death involved in the OXYS retinopathy initiation and progression. Retinal mRNA profiles of 20-day-old OXYS and Wistar rats were generated at the sequencing read depth 40 mln, in triplicate, using Illumina GAIIx. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay was performed to measure the apoptosis level. GeneMANIA was used to construct interaction networks for differentially expressed (DE) apoptosis-related genes at ages 20 d and 3 and 18 months. Functional analysis was suggestive of a developmental process, signal transduction, and cell differentiation as the most enriched biological processes among 245 DE genes at age 20 d An increased level of apoptosis was observed in OXYS rats at age 20 d but not at advanced stages. We identified functional clusters in the constructed interaction networks and possible hub genes (Rasa1, cFLAR, Birc3, Cdk1, Hspa1b, Erbb3, and Ntf3). We also demonstrated the significance of the extrinsic apoptotic pathway at preclinical, early, and advanced stages of retinopathy development. Besides the cell death signaling pathways, immune system-related processes and lipid-metabolic processes showed overrepresentation in the clusters of all networks. These characteristics of the expression profile of the genes functionally associated with apoptosis may contribute to the pathogenesis of AMD-like retinopathy in senescence-accelerated OXYS rats.

Keywords: OXYS rats; RNA-Seq; age-related macular degeneration; aging; apoptosis; cell death; retinal transcriptome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Baculoviral IAP Repeat-Containing 3 Protein
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • CDC2 Protein Kinase
  • Cell Differentiation
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Ontology
  • Gene Regulatory Networks*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • High-Throughput Nucleotide Sequencing
  • In Situ Nick-End Labeling
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Macular Degeneration / genetics*
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Male
  • Molecular Sequence Annotation
  • Multigene Family
  • Nucleocytoplasmic Transport Proteins / genetics
  • Nucleocytoplasmic Transport Proteins / metabolism
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Transgenic
  • Rats, Wistar
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism
  • Retina / metabolism*
  • Retina / pathology
  • p120 GTPase Activating Protein / genetics
  • p120 GTPase Activating Protein / metabolism


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • HSP70 Heat-Shock Proteins
  • Hspa2 protein, rat
  • Inhibitor of Apoptosis Proteins
  • Nucleocytoplasmic Transport Proteins
  • RNA, Messenger
  • p120 GTPase Activating Protein
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Birc3 protein, rat
  • Receptor, ErbB-3
  • CDC2 Protein Kinase
  • Cdk1 protein, rat
  • Cyclin-Dependent Kinases