PUBLICATION
Pharmacological restoration of visual function in a zebrafish model of von-Hippel Lindau disease
- Authors
- Ward, R., Ali, Z., Slater, K., Reynolds, A.L., Jensen, L.D., Kennedy, B.N.
- ID
- ZDB-PUB-190303-9
- Date
- 2019
- Source
- Developmental Biology 457(2): 226-234 (Journal)
- Registered Authors
- Kennedy, Breandan N., Reynolds, Alison
- Keywords
- Retinal neovascularisation, Sunitinib malate, VHL, Von Hippel-Lindau, Zebrafish
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology
- Blindness/genetics
- Disease Models, Animal
- Eye/blood supply*
- Eye/embryology
- Hemangioblastoma/genetics
- Retina/embryology*
- Sunitinib/pharmacology
- Tumor Suppressor Proteins/genetics*
- Vision, Ocular/genetics
- Zebrafish/genetics*
- Zebrafish Proteins/genetics*
- von Hippel-Lindau Disease/genetics*
- von Hippel-Lindau Disease/pathology
- von Hippel-Lindau Disease/prevention & control
- PubMed
- 30825427 Full text @ Dev. Biol.
Citation
Ward, R., Ali, Z., Slater, K., Reynolds, A.L., Jensen, L.D., Kennedy, B.N. (2019) Pharmacological restoration of visual function in a zebrafish model of von-Hippel Lindau disease. Developmental Biology. 457(2):226-234.
Abstract
Von Hippel-Lindau (VHL) syndrome is rare, autosomal dominant disorder, characterised 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 neovascularisation of the brain, eye and trunk together with oedema 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 an endogenous molecular barrier that prevents development of intraretinal vasculature, and that pharmacological intervention with sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal vessels in vhl-/- zebrafish.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping