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

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

Author information

1
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.
2
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States.
3
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
4
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States.

Abstract

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

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