Abstract
BackgroundMitotic 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).ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2477-9) contains supplementary material, which is available to authorized users.
Highlights
Mitotic terminally differentiated photoreceptors (PRs) are observed in early retinal degeneration, an inherited canine retinal disease driven by mutations in the NDR kinase serine/threonine kinase 38 like (STK38L) (NDR2)
The results showed similar trends for both phospho histone H3 (PHH3) and proliferative cell nuclear antigen (PCNA) labeling in the different models and in normals (Fig. 2a and b, respectively), the number of PCNApositive cells was lower than the number of PHH3positive cells at every time point examined
In summary, our results show that in early phases of three retinal degenerative diseases in dogs, PHH3 labeling is present in the outer nuclear layer, an indication that a subset of PR cells have entered the M-phase of the cell cycle
Summary
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). Photoreceptor (PR) cells are specialized retinal neurons that efficiently capture light and transduce it into a neural signal Their intricate and highly specific structure is dependent on the expression of multiple genes, including those involved in PR specification, differentiation and maintenance [1]. A recent comprehensive analysis of different rodent retinal mutants, along with a light-induced retinal degeneration model, clearly demonstrated that reactivation of the expression of cell cycle genes did not correlate with PR cell division as determined by ethynyl deoxyuridine incorporation and phospho histone H3 (PHH3) labeling. Instead, this process was essential to promote the cell death pathways [15]. Under some specific circumstances [16], a limited number of PRs and other neurons can be generated from presumably terminally differentiated Müller cells that dedifferentiate, proliferate and express neuronal progenitor markers in the adult rat, mouse as well as chicken and fish (see for review [17])
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