Dlg1 activates beta-catenin signaling to regulate retinal angiogenesis and the blood-retina and blood-brain barriers

Elife. 2019 May 8:8:e45542. doi: 10.7554/eLife.45542.


Beta-catenin (i.e., canonical Wnt) signaling controls CNS angiogenesis and the blood-brain and blood-retina barriers. To explore the role of the Discs large/membrane-associated guanylate kinase (Dlg/MAGUK) family of scaffolding proteins in beta-catenin signaling, we studied vascular endothelial cell (EC)-specific knockout of Dlg1/SAP97. EC-specific loss of Dlg1 produces a retinal vascular phenotype that closely matches the phenotype associated with reduced beta-catenin signaling, synergizes with genetically-directed reductions in beta-catenin signaling components, and can be rescued by stabilizing beta-catenin in ECs. In reporter cells with CRISPR/Cas9-mediated inactivation of Dlg1, transfection of Dlg1 enhances beta-catenin signaling ~4 fold. Surprisingly, Frizzled4, which contains a C-terminal PDZ-binding motif that can bind to Dlg1 PDZ domains, appears to function independently of Dlg1 in vivo. These data expand the repertoire of Dlg/MAGUK family functions to include a role in beta-catenin signaling, and they suggest that proteins other than Frizzled receptors interact with Dlg1 to enhance beta-catenin signaling.

Keywords: blood-brain barrier; blood-retina barrier; canonical Wnt signaling; developmental biology; genetics; genomics; mouse; mouse genetics; retinal angiogenesis; vascular endothelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier*
  • Blood-Retinal Barrier*
  • Discs Large Homolog 1 Protein / metabolism*
  • Endothelial Cells / physiology
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Retina / growth & development*
  • beta Catenin / metabolism*


  • Discs Large Homolog 1 Protein
  • Dlg1 protein, mouse
  • beta Catenin