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Harald Gjerde, Lucia Cáceres, Michael Ngo, Elizabeth Cairns, Sergey Prykhozhij, Sarah van der Ende, Christopher McMaster, Jason Berman, Johane M Robitaille; Characterization of Retinal Vascular Development in fzd4-/- Zebrafish with Familial Exudative Vitreoretinopathy (FEVR). Invest. Ophthalmol. Vis. Sci. 2019;60(9):6058. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Familial exudative vitreoretinopathy (FEVR) is a rare, incurable genetic disorder characterized by reduced peripheral retinal vascularization during development. Half of FEVR cases are due to Norrin-FZD4 signaling mutations. We generated a fzd4-/- zebrafish model using transcription activator-like effector nucleases (TALEN) technology, with the goal of screening compounds that ameliorate this vascular defect.
The eyes of WT and fzd4-/- zebrafish were enucleated at weeks 1-12, 32, 48 post-fertilization. GFP+ fluorescent vessels were imaged using a Zeiss stereomicroscope. In addition to qualitative comparisons, the images were analyzed with ImageJ software. Optokinetic responses were elicited under white light with a spatial frequency and velocity of 0.04 cycles per degree (cpd) and 25-30rpm/sec, respectively.
Zebrafish retinal vasculature is asymmetrically distributed along the dorsoventral axis, with active vascular remodeling in the ventral hemisphere of the retina throughout development. fzd4-/- mutants exhibit disorganized vascular patterning with discernable tubular fusion by week 8 of development in the ventral retina. Corresponding to these structural changes, optokinetic assays reveal that fzd4-/- mutants have impaired optokinetic response requiring increased illumination for compensation.
Vascular disorganization in fzd4-/- retinas appeared at week 8 in the ventral hemisphere of the retina. We have generated visually impaired zebrafish FEVR mutants that exhibit abnormal retinal vascular development. Fzd4-/- fish do not show early manifestations of disease, suggesting that techniques such as morpholinos in the study of candidate FEVR genes may miss relevant genes that contribute to FEVR pathology. These fish provide a tractable model for studying the blood vessel biology in disorders of retinal vascular development and may serve as a preclinical tool for evaluating therapeutic interventions.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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