Frizzled 4 regulates ventral blood vessel remodeling in the zebrafish retina.
Animals
Animals, Genetically Modified
Body Patterning
/ genetics
Disease Models, Animal
Embryo, Nonmammalian
Familial Exudative Vitreoretinopathies
/ diagnosis
Feasibility Studies
Frizzled Receptors
/ genetics
Humans
Neovascularization, Pathologic
/ embryology
Retina
/ diagnostic imaging
Retinal Diseases
/ genetics
Retinal Vessels
/ embryology
Vascular Remodeling
/ genetics
Zebrafish
/ embryology
Zebrafish Proteins
/ genetics
FEVR
optokinetic response
pericytes
retinal vasculature
Journal
Developmental dynamics : an official publication of the American Association of Anatomists
ISSN: 1097-0177
Titre abrégé: Dev Dyn
Pays: United States
ID NLM: 9201927
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
14
03
2019
revised:
04
09
2019
accepted:
06
09
2019
pubmed:
1
10
2019
medline:
27
5
2020
entrez:
1
10
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
Frizzled Receptors
0
Zebrafish Proteins
0
fzd4 protein, zebrafish
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1243-1256Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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