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

• Published in: Nature communications 2017-07, Vol.8 (1), p.16050-16050, Article 16050
• Main Authors: Zhang, Chi, Lai, Maria B., Khandan, Lavan, Lee, Lindsey A., Chen, Zhe, Junge, Harald J.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/51; 13/95; 14/19; 631/136/16; 64/60; Angiogenesis; Animals; ATPases Associated with Diverse Cellular Activities - metabolism; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain; Cargo compartments; Central nervous system; Control systems; Defects; Endocytosis; Endosomal Sorting Complexes Required for Transport - metabolism; Endosomes - metabolism; Endothelial cells; Endothelial Cells - metabolism; Exudation; Eye Diseases, Hereditary - genetics; Eye Diseases, Hereditary - metabolism; Eye Proteins - genetics; Eye Proteins - metabolism; Familial exudative vitreoretinopathy; Frizzled protein; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; In vitro methods and tests; In Vitro Techniques; Internalization; Ligands; Lysosomes - metabolism; Mice; multidisciplinary; Multivesicular Bodies - metabolism; Mutation; Neovascularization, Physiologic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous system; Protein Transport; Receptors; Retina; Retinal Diseases - genetics; Retinal Diseases - metabolism; Retinal Vessels - growth & development; Science; Science (multidisciplinary); Signal transduction; Signaling; Transport processes; Ubiquitination; Vacuolar Proton-Translocating ATPases - metabolism; Wnt protein; Wnt Signaling Pathway; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms16050

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. Multiple mechanisms regulate Wnt/ß-catenin signalling. Zhang et al . describe a novel regulatory pathway and show that the activator of canonical Wnt signalling, Norrin, triggers endocytosis of its receptor Frizzled4 by promoting Frizzled4 ubiquitination.