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Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations

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Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations University of Pennsylvania ScholarlyCommons Departmental Papers (Vet) School of Veterinary Medicine 3-11-2016 Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations Kristin L. Gardiner University of Pennsylvania Louise Downs University of Pennsylvania Agnes I. Berta-Antalics University of Pennsylvania Evelyn Santana University of Pennsylvania Gustavo D. Aguirre University of Pennsylvania, [email protected] See next page for additional authors Follow this and additional works at: https://repository.upenn.edu/vet_papers Part of the Veterinary Medicine Commons Recommended Citation Gardiner, K. L., Downs, L., Berta-Antalics, A. I., Santana, E., Aguirre, G. D., & Genini, S. (2016). Photoreceptor Proliferation and Dysregulation of Cell Cycle Genes in Early Onset Inherited Retinal Degenerations. BMC Genomics, 17 (221), http://dx.doi.org/10.1186/s12864-016-2477-9 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/vet_papers/152 For more information, please contact [email protected]. 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 MOB1and 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. Keywords Canine models, cell cycle, erd, hippo pathway, photoreceptor degeneration, photoreceptor mitosis, rcd1, xlpra2 Disciplines Medicine and Health Sciences | Veterinary Medicine Author(s) Kristin L. Gardiner, Louise Downs, Agnes I. Berta-Antalics, Evelyn Santana, Gustavo D. Aguirre, and Sem Genini This journal article is available at ScholarlyCommons: https://repository.upenn.edu/vet_papers/152 Gardiner et al. BMC Genomics (2016) 17:221 DOI 10.1186/s12864-016-2477-9 RESEARCH ARTICLE Open Access Photoreceptor proliferation and dysregulation of cell cycle genes in early onset inherited retinal degenerations Kristin L. Gardiner1, Louise Downs1, Agnes I. Berta-Antalics1,2, Evelyn Santana1, Gustavo D. Aguirre1* and Sem Genini1* 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. Keywords: Canine models, Cell cycle, erd, Hippo pathway, Photoreceptor degeneration, Photoreceptor mitosis, rcd1, xlpra2 Background mutation and disease is limited. Moreover, while apoptotic Photoreceptor (PR) cells are specialized retinal neurons that cell death is the final common pathway in most retinal de- efficiently capture light and transduce it into a neural signal. generative diseases [7], the rate of degeneration and cell Their intricate and highly specific structure is dependent death pathway utilized varies in a disease, mutation and on the expression of multiple genes, including those species-specific manner, demonstrating a high level of com- involved in PR specification, differentiation and mainten- plexity [8–13]. Identifying the principal molecular players ance [1]. Indeed, ~300 genes and loci are involved in retinal and providing an in-depth knowledge of the mechanisms degeneration in man (RetNet: http://www.sph.uth.tmc.edu/ that induce and regulate the underlying PR cell death will RetNet/; October 2015), and a lower but still substantial provide essential insight into disease progression. This will number of genes in animals [2, 3]. While mutations in PR- help to develop pharmacological agents and specific therap- specific or enriched genes are common, and cause a broad ies that provide PR protection in the hopes of treating spectrum of inherited retinal diseases (reviewed by [4–6]), inherited retinopathies. an understanding of the mechanistic links between While stimulating the proliferation of diseased yet functional PRs to maintain the PR layer would likely be * Correspondence: [email protected]; [email protected] therapeutically beneficial in some retinal degenerative 1 Section of Ophthalmology, Department of Clinical Studies, School of diseases, the proliferative potential of PR cells is contro- Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104, USA versial, and not well understood. PRs are terminally Full list of author information is available at the end of the article © 2016 Gardiner et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gardiner et al. BMC Genomics (2016) 17:221 Page 2 of 18 differentiated, and undergo their final cell division just To this end, we examined the retinal and retinal pig- prior to cell fate specification; compensatory neurogen- ment epithelium (RPE) expression of selected genes and esis mechanisms do not exist to replace all dying cells in proteins that are involved in cell cycle regulation, or be- the normal retina [1]. Indeed, it was originally postulated long to the NDR protein-kinase family and the Hippo that new PRs are generated in naturally occurring retinal pathway [15, 21]. Notably, our results indicate that PR diseases, however this hypothesis has been disproved [14]. proliferation also occurred in xlpra2 and rcd1, but that Furthermore, a recent comprehensive analysis of different formation of hybrid rod/S-cones is unique to erd. Fur- rodent retinal mutants, along with a light-induced retinal thermore, we demonstrate a concurrent dysregulation of degeneration model, clearly demonstrated that reactiva- critical cell cycle genes that were differentially expressed tion of the expression of cell cycle genes did not correlate (DE) in all three diseases, while Hippo pathway genes with PR cell division as determined by ethynyl deoxyuri- were more specifically altered in erd. dine incorporation and phospho histone H3 (PHH3) label- ing. Instead, this process was essential to promote the cell Results death pathways [15]. In contrast, under some specific Morphology of early-onset canine retinal degeneration circumstances [16], a limited number of PRs and other models neurons can be generated from presumably terminally We initially characterized the retinal morphology of the differentiated Müller cells that dedifferentiate, proliferate 3 early-onset disease models that generally have a similar and express neuronal progenitor markers in the adult rat, pattern of PR development and degeneration (Fig. 1). mouse as well as chicken and fish (see for review [17]). Although overall retinal development is initially normal In contrast to normal PRs and other disease models, (2 wks, data not shown), there were differences in the we recently reported that a mutation in the NDR family subsequent rates and kinetics of
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