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

Chris Cho, Yanshu Wang, Philip M. Smallwood, John Williams, Jeremy Nathans

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - May 8 2019

Fingerprint

beta Catenin
Blood-Brain Barrier
Retina
Blood
Guanylate Kinases
Endothelial cells
Clustered Regularly Interspaced Short Palindromic Repeats
Endothelial Cells
Frizzled Receptors
PDZ Domains
Phenotype
Retinal Vessels
Transfection
Brain
Proteins

Keywords

  • blood-brain barrier
  • blood-retina barrier
  • canonical Wnt signaling
  • developmental biology
  • genetics
  • genomics
  • mouse
  • mouse genetics
  • retinal angiogenesis
  • vascular endothelial cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Dlg1 activates beta-catenin signaling to regulate retinal angiogenesis and the blood-retina and blood-brain barriers. / Cho, Chris; Wang, Yanshu; Smallwood, Philip M.; Williams, John; Nathans, Jeremy.

In: eLife, Vol. 8, 08.05.2019.

Research output: Contribution to journalArticle

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