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Coco Ke Jiang, Matthew Brooks, Gökhan Karakülah, Linn Gieser, Jung-Woong Kim, Alexis Boleda, Anand Swaroop; A Search for Common Pre-apoptotic Signals/Pathways in Mouse Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):267.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited photoreceptor degenerations are characterized by progressive death of mutant photoreceptors (PRs). To date, mutations in over 220 genes that encode proteins with broad spectrum of biological roles in PRs have been associated with these genetically and phenotypically heterogeneous diseases, which remain largely incurable, and no effective treatment is as yet available. The mystery remains why disruptions in diverse classes of proteins eventually lead to PR death. It is unlikely that each different mutation has a unique mechanism/pathway in triggering PR cell death. A more parsimonious model is that there is one, or a few, critical genes or pathways altered by different mutation loci, whereby mutant PRs in each case adopt a pre-death status, leading to cell death (Swaroop et al. Nat Rev Neurosci 2010). Therefore, in seeking the ultimate cause of mutant PR death and, more importantly, a potential general therapy, we set the goal to identify convergent pre-apoptotic signals that determine the death fate of PRs, shared by different retinal degeneration (RD) models carrying distinct mutations of various classes.
We chose six RD mouse models in this study: Aipl1 KO, Rpgrip KO, Rd1 (Pde6brd1), Rd10 (Pde6brd10), Rd16 (Cep290rd16) and Rds (Prph2Rd2). Each mutant mouse was crossed to the Nrlp-EGFP mice to obtain a pure GFP+ rod population through cell sorting. Using next generation sequencing (RNAseq), the transcriptome profiles of mutant PRs were analyzed at various stages with focus on early postnatal ages (prior to and during the early phase of generation). Age matched Nrlp-EGFP mice served as wild type controls.
A total number of 133 samples were obtained and sequenced. The transcriptome profiles of each sample from different models at specific ages will be compared to each other and to wild type controls, aiming to identify common pre-apoptotic signals. The focus will be on genes or pathways showing similar dynamics (based on time and degeneration state) in different mutant PRs. We will take either the de novo approach, focusing on global network analysis by comparing each pair of samples, or take candidate gene group or pathway-based approach.
The identified pre-apoptotic signals might potentially be the convergent node in regulating mutant PR survival/death and might be used as target(s) for developing a common therapy for inherited photoreceptor degenerations.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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