Norrin-induced Frizzled4 endocytosis and endo-lysosomal trafficking control retinal angiogenesis and barrier function

Chi Zhang, Maria B. Lai, Lavan Khandan, Lindsey A. Lee, Zhe Chen, Harald J. Junge

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Angiogenesis and blood-brain barrier formation are required for normal central nervous system (CNS) function. Both processes are controlled by Wnt or Norrin (NDP) ligands, Frizzled (FZD) receptors, and β-catenin-dependent signalling in vascular endothelial cells. In the retina, FZD4 and the ligand NDP are critical mediators of signalling and are mutated in familial exudative vitreoretinopathy. Here, we report that NDP is a potent trigger of FZD4 ubiquitination and induces internalization of the NDP receptor complex into the endo-lysosomal compartment. Inhibition of ubiquitinated cargo transport through the multivesicular body (MVB) pathway using a dominant negative ESCRT (endosomal sorting complexes required for transport) component VPS4 EQ strongly impairs NDP/FZD4 signalling in vitro and recapitulates CNS angiogenesis and blood-CNS-barrier defects caused by impaired vascular β-catenin signalling in mice. These findings provide evidence for an important role of FZD4 endocytosis in NDP/FZD4 signalling and in CNS vascular biology and disease.

Original languageEnglish (US)
Article number16050
JournalNature communications
Volume8
DOIs
StatePublished - Jul 4 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by ACS IRG #57-001-53 from the American Cancer Society, the Boettcher Foundation Webb-Waring Biomedical Research Award (to H.J.J.), and a grant from the NIH (R01EY024261 to H.J.J.).

Publisher Copyright:
© 2017 The Author(s).

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