Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States
Yanshu Wang
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
Philip M Smallwood
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
John Williams
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States
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.
