Vascular endothelial-cadherin plays a role in regulating the norrin-FZD4 pathway and can cause familial exududative-vitroretinopathy (FEVR)

1 online resource (41 p.) : ill. (chiefly col.)Includes abstract.Includes bibliographical references (p. 36-41).FEVR is a genetic disorder that causes abnormal vascularization of the retina, which can lead to retinal detachment and blindness. Mutations in the genes encoding Norrin, LRP5, FZD4 and TSPAN12 can cause FEVR. Interestingly, these genes encode proteins that belong to the Norrin-FZD4 signalling pathway that ultimately activate [beta]-catenin to upregulate gene transcription. Mutations in the pathway are thought to cause FEVR due to the lack of [beta]-catenin translocating to the nucleus, however the mutations described only account for 50% of cases whereas the other half is due to unknown genes. In a cohort of 123 FEVR patients, a proband was found to have a mutation in the vascular endothelial cadherin (VE-cadherin), this mutation is at position 775 where a glycine has been substituted with a serine (G775S).Our objective is to provide evidence that VE-cadherin (CDH5) plays a role in the Norrin-FZD4 pathway by determining whether wild type or mutant VE-cadherin have an effect on [beta]-catenin binding, determine whether VE-cadhrin (CDH5) interacts with LRP5, and determine whether mutant VE-cadherin has a defect in internalization. In FEVR mouse models, FZD4-/-and TSPAN12-/-mice had increased VE-cadherin protein expression, as well as increased src activation and poly-ubiquination of VE-cadherin. Immunoprecipitation assays were used to determine whether mutant VE-cadherin had an effect on [beta]-catenin binding. There was no difference in binding between wild-type and mutant VE-cadherin when transfected in HEK293 cells. Cells expressing wild-type VE-cadherin immunoprecipitated with LRP5, whereas G775S did not interact with LRP5. The data suggests that VE-cadherin may play a role in regulating the Norrin-FZD4 pathway and interacting with LRP5