gms | German Medical Science

Objective: The retinal degeneration 10 (rd10) mouse model has become relevant in ophthalmic research because of its similarities to retinitis pigmentosa. In this model a progressive rod-predominant photoreceptor cell death occurs due to a mutation in the gene encoding the beta-subunit of the rod phosphodiesterase. Rods start to degenerate at P16. Cell death peaks between P21-P25 and by P60 only cones have survived. Afterwards, a remodelling of the remnant neural retina sets in. Our study aims to analyse the regulatory changes on gene expression level at different development stages up to the final phase of remodelling.

Methods: Total RNA was isolated from retinas of rd10 and wild-type (wt) mice at defined ages of P18, P25, P35, P61, post-natal month (PNM) 5 and PNM10. The transcriptome-wide gene expression profiles were analysed using microarray assays. In addition, selected genes were evaluated by quantitative real-time PCR (RT-qPCR) and the synthesis of the encoded proteins was analysed by immunoblotting.

Results: Microarray-based transcriptome analysis showed significant regulation of about 9100 coding sequences in P61 rd10 mice compared to the wt. Microarray analysis and RT-qPCR confirmed the down-regulation of genes involved in phototransduction (e.g. SAG) and the morphogenesis of photoreceptor discs (e.g. FSCN2). In contrast, genes related to gliosis (e.g. GFAP) and regulation of the complement cascade (e.g. SERPING1) were up-regulated. Especially in young rd10 retinas, SERPINA3, a gene associated with various human diseases (e.g. alpha-1 antitrypsin deficiency), was one of the most significantly up-regulated genes.

Discussion: Our data offer comprehensive insights into the genetics underlying and accompanying the degeneration and remodelling processes in retinas of aging rd10 mice. Further data evaluation is required to identify disease-specific key genes and pathways that could be controlled or potentially serve as targets for a gene-based therapeutic approach.