Photoreceptor proliferation and dysregulation of cell cycle genes in early onset inherited retinal degenerations

作者：Gardiner Kristin L; Downs Louise; Berta Antalics Agnes I; Santana Evelyn; Aguirre Gustavo D; Genini Sem^*

来源：BMC Genomics, 2016, 17(1): 221.

DOI：10.1186/s12864-016-2477-9

• Canine models
• Cell cycle
• erd
• Hippo pathway
• Photoreceptor degeneration
• Photoreceptor mitosis
• rcd1
• xlpra2

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 Muller 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.

• 出版日期2016-3-11