Frizzled 4 regulates ventral blood vessel remodeling in the zebrafish retina

Abstract

Background Familial exudative vitreoretinopathy (FEVR) is a rare congenital disorder characterized by a lack of blood vessel growth to the periphery of the retina with secondary fibrovascular proliferation at the vascular‐avascular junction. These structurally abnormal vessels cause leakage and hemorrhage, while the fibroproliferative scarring results in retinal dragging, detachment and blindness. Mutations in the FZD4 gene represent one of the most common causes of FEVR. Methods A loss of function mutation resulting from a 10‐nucleotide insertion into exon 1 of the zebrafish fzd4 gene was generated using transcription activator‐like effector nucleases (TALENs). Structural and functional integrity of the retinal vasculature was examined by fluorescent microscopy and optokinetic responses. Results Zebrafish retinal vasculature is asymmetrically distributed along the dorsoventral axis, with active vascular remodeling on the ventral surface of the retina throughout development. fzd4 mutants exhibit disorganized ventral retinal vasculature with discernable tubular fusion by week 8 of development. Furthermore, fzd4 mutants have impaired optokinetic responses requiring increased illumination. Conclusion We have generated a visually impaired zebrafish FEVR model exhibiting abnormal retinal vasculature. These fish provide a tractable system for studying vascular biology in retinovascular disorders, and demonstrate the feasibility of using zebrafish for evaluating future FEVR genes identified in humans.

Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism

“…[ 32 , 33 , [60] , [61] , [62] , [63] ]. Furthermore, vascular mural cell dropout has long been theorized to be a key player in microvascular homeostasis and recent studies have shown that loss of mural cells increases the susceptibility of the retinal vasculature to VEGF signaling and retinal angiogenesis [ 26 , [64] , [65] , [66] ]. Thus, the onset of retinopathy in aldh2.1 −/− larvae and adults was driven by an altered regulation of the MAPK family members and reduction of vascular mural cell coverage through the reactive metabolite AA independently of hyperglycemia.…”

Ocular phenotype and genetical analysis in patients with retinopathy of prematurity

“…It consists of a N-terminal extracellular cysteine-rich domain, seven transmembrane domains, extracellular/intracellular loops, and a C-terminal intracellular domain [ 28 ]. Frizzled-4 plays the role of receptor to bind specific ligands, which is essential for initiating different signaling pathways, such as canonical Wnt/β-catenin pathway, planar cell polarity pathway, and Wnt/Ca 2+ pathway, this signaling pathway impairments could cause defective tissue homeostasis or cell proliferation in retina [ 29 ].…”

Advancing Diabetic Retinopathy Research: Analysis of the Neurovascular Unit in Zebrafish

“…Recently, to research the function of the frizzled4 gene, which is implicated in the development of familial exudative vitreoretinopathy (FEVR), one study found that pericytes in the zebrafish retina contain frizzled4 mRNA and have a very unique position on the retinal vasculature [80]. These observations could finally make the quantification of pericyte numbers in the zebrafish retina possible.…”

“…However, as mentioned above, this marker cannot reliably stain pericytes on zebrafish retinal vessels. With the discussed transgenic reporter lines for vascular mural cells in zebrafish, and the recent confirmation of the morphology and localisation of pericytes in zebrafish [80], this should change in the future. Future research should elucidate how pericytes behave in diabetic or other pathological conditions in zebrafish, revealing more about their function and potentially making them a target for further research.…”