title: Photoreceptor proliferation and dysregulation of cell cycle genes in early onset inherited retinal degenerations.
abstract: BACKGROUND
  Mitotic terminally differentiated photoreceptors (PRs) are observed in early retinal degeneration (erd), an inherited canine retinal disease driven by mutations in the NDR kinase STK38L (NDR2).
  
  
  RESULTS
  We demonstrate that a similar proliferative response, but of lower magnitude, occurs in two other early onset disease models, X-linked progressive retinal atrophy 2 (xlpra2) and rod cone dysplasia 1 (rcd1). Proliferating cells are rod PRs, and not microglia or Müller cells. Expression of the cell cycle related genes RB1 and E2F1 as well as CDK2,4,6 was up-regulated, but changes were mutation-specific. Changes in cyclin expression differed across all genes, diseases and time points analyzed, although CCNA1 and CCNE1 expression increased with age in the three models suggesting that there is a dysregulation of cell cycle gene expression in all three diseases. Unique to erd, however, are mutation-specific changes in the expression of NDR kinases and Hippo signaling members with increased expression of MOB1 and LATS1 in the newly generated hybrid rod/S-cones.
  
  
  CONCLUSIONS
  Our data raise the intriguing possibility that terminally differentiated normal PRs are kept from dividing by NDR2-MOB1 interaction. Furthermore, they provide the framework for the selection of candidate genes for further investigation as potential targets of therapy.
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Gardiner
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Downs
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA.|Augenklinik Uniklinik Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Agnes I
authors.initials: AI
authors.lastname: Berta-Antalics
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Santana
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA. geninis@vet.upenn.edu.
authors.forename: Sem
authors.initials: S
authors.lastname: Genini
mesh_terms: D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D016213:Cyclins / Q000235:genetics; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D050687:E2F1 Transcription Factor / Q000235:genetics; D018816:Genes, cdc; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D010786:Photoreceptor Cells / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000662:veterinary*; D016160:Retinoblastoma Protein / Q000235:genetics
chemical_list: D016213:Cyclins; D050687:E2F1 Transcription Factor; D010750:Phosphoproteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases
keywords: Canine models; Cell cycle; Hippo pathway; Photoreceptor degeneration; Photoreceptor mitosis; erd; rcd1; xlpra2