Zebrafish Models of Photoreceptor Dysfunction and Degeneration

Abstract

Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review the wealth of information from existing zebrafish models of photoreceptor disease, specifically as they relate to currently accepted taxonomic classes of human rod and cone disease. We also highlight that rich, detailed information can be derived from studying photoreceptor development, structure, and function, including behavioural assessments and in vivo imaging of zebrafish. Zebrafish models are available for a diversity of photoreceptor diseases, including cone dystrophies, which are challenging to recapitulate in nocturnal mammalian systems. Newly discovered models of photoreceptor disease and drusenoid deposit formation may not only provide important insights into pathogenesis of disease, but also potential therapeutic approaches. Zebrafish have already shown their use in providing pre-clinical data prior to testing genetic therapies in clinical trials, such as antisense oligonucleotide therapy for Usher syndrome.

Keywords: Danio rerio; Leber congenital amaurosis; choroideremia; cone dystrophy; cone-rod dystrophy; inherited photoreceptor disease; macular degeneration; regeneration; retinal neovascularization; retinitis pigmentosa.

Figure 1

Anatomy of rod and cone photoreceptors and their organization in the human retina. (A) Cartoons of a rod (grey) and cone (blue) photoreceptor. Photoreceptors have an outer segment (OS) that is packed with light-sensitive opsin proteins, a connecting cilium (CC) that connects the OS with the mitochondria-rich inner segment (IS), a cell body (CB), and a synapse. (B) Cartoon of the human photoreceptor mosaic. Humans have three types of cones: red, green, and blue, depicted in those respective colours. The peripheral retina is rod-dense with cones interspersed throughout, while the central retina is cone-dense.

Figure 2

Zebrafish photoreceptor organization. (A) Cartoon depiction of the adult zebrafish photoreceptor mosaic. UV and blue cones, depicted in purple and blue respectively, alternate in their rows while red and green double cones alternate in neighbouring rows. Rods are studded throughout. (B) Fluorescent image of a flat-mounted adult transgenic zebrafish retina, with GFP expressed in UV cones (magenta) and mCherry expressed in blue cones (cyan). The alternation of UV and blue cones in their rows is apparent. (C) Immunofluorescent image of a cryosectioned adult Tg(sws1:GFP) zebrafish retina with GFP in UV cones (green). UV opsin (red) and rhodopsin (magenta) are labelled, as well as nuclei (cyan).