Pharmacological Restoration of Visual Function in a Zebrafish Model of von-Hippel Lindau Disease

Abstract

Von Hippel-Lindau (VHL) syndrome is rare, autosomal dominant disorder, characterized by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality of Vhl -/mice in utero restricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in the vhl gene represent a viable, alterative vertebrate model to investigate associated ocular loss-of-function phenotypes. Previous studies reported neovascularization of the brain, eye and trunk together with odema in the vhl -/zebrafish eye. In this study, we demonstrate vhl -/zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in the vhl -/eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed in vhl -/zebrafish. We conclude that the zebrafish vhl gene contributes to the endogenous molecular barrier that prevents development of intraretinal vasculature and that sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal and choroidal vessels in vhl -/zebrafish.

Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision

“…Larvae treated with emixustat and fenretinide in the dark were morphologically normal, other than they did not inflate their swim bladder ( Figure 2D) as also observed under a normal light/dark cycle ( Figure 1C). An uninflated swim bladder is commonly observed in visually compromised zebrafish larvae (40,41). Interestingly, neither 50 μM emixustat nor 10 μM fenretinide induced obvious changes in retinal histology, particularly the photoreceptor outer segment structure and RPE, compared to vehicle controls (Figure 2E-G, 2E'-2G').…”

Simultaneous analysis of neuroactive compounds in zebrafish

“…Zebrafish larvae and embryos have long been used to assay environmental toxicants (10,11) and as models for vision (12)(13)(14)(15)(16), threat response (17), memory (18), algesia (19)(20)(21), and sleep (22)(23)(24). These successes in the laboratory have extended to the clinic: In a rare example of bench-to-bedside, the FDA approved lorcaserin as an antiepileptic, based significantly on evidence in zebrafish (25).…”