Interplay of the Norrin and Wnt7a/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance

Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11827-E11836. doi: 10.1073/pnas.1813217115. Epub 2018 Nov 26.


β-Catenin signaling controls the development and maintenance of the blood-brain barrier (BBB) and the blood-retina barrier (BRB), but the division of labor and degree of redundancy between the two principal ligand-receptor systems-the Norrin and Wnt7a/Wnt7b systems-are incompletely defined. Here, we present a loss-of-function genetic analysis of postnatal BBB and BRB maintenance in mice that shows striking threshold and partial redundancy effects. In particular, the combined loss of Wnt7a and Norrin or Wnt7a and Frizzled4 (Fz4) leads to anatomically localized BBB defects that are far more severe than observed with loss of Wnt7a, Norrin, or Fz4 alone. In the cerebellum, selective loss of Wnt7a in glia combined with ubiquitous loss of Norrin recapitulates the phenotype observed with ubiquitous loss of both Wnt7a and Norrin, implying that glia are the source of Wnt7a in the cerebellum. Tspan12, a coactivator of Norrin signaling in the retina, is also active in BBB maintenance but is less potent than Norrin, consistent with a model in which Tspan12 enhances the amplitude of the Norrin signal in vascular endothelial cells. Finally, in the context of a partially impaired Norrin system, the retina reveals a small contribution to BRB development from the Wnt7a/Wnt7b system. Taken together, these experiments define the extent of CNS region-specific cooperation for several components of the Norrin and Wnt7a/Wnt7b systems, and they reveal substantial regional heterogeneity in the extent to which partially redundant ligands, receptors, and coactivators maintain the BBB and BRB.

Keywords: central nervous system; mouse genetics; vascular endothelial cells; β-catenin signaling.

Publication types

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

MeSH terms

  • Animals
  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / growth & development*
  • Blood-Brain Barrier / physiology*
  • Blood-Retinal Barrier / cytology
  • Blood-Retinal Barrier / growth & development*
  • Blood-Retinal Barrier / physiology*
  • Cell Culture Techniques
  • Eye Proteins / genetics
  • Eye Proteins / physiology*
  • Frizzled Receptors / deficiency
  • Frizzled Receptors / genetics
  • Frizzled Receptors / physiology
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Models, Neurological
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Signal Transduction
  • Tetraspanins / deficiency
  • Tetraspanins / genetics
  • Tetraspanins / physiology
  • Wnt Proteins / deficiency
  • Wnt Proteins / genetics
  • Wnt Proteins / physiology*
  • beta Catenin / physiology


  • CTNNB1 protein, mouse
  • Eye Proteins
  • Frizzled Receptors
  • Fzd4 protein, mouse
  • Ndph protein, mouse
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Tetraspanins
  • Tspan12 protein, mouse
  • Wnt Proteins
  • Wnt7a protein, mouse
  • Wnt7b protein, mouse
  • beta Catenin