Contributed by Jeremy Nathans, October 23, 2018 (sent for review August 2, 2018; reviewed by Chenghua Gu and Brad St. Croix)
The blood–brain barrier (BBB) and the blood–retina barrier (BRB) play essential roles in maintaining the health of the central nervous system. Two partially redundant ligand–receptor systems—the Norrin and Wnt7a/Wnt7b systems—activate β-catenin signaling in vascular endothelial cells to control BBB and BRB development and maintenance. The present study explores the partially overlapping roles of these two systems in the postnatal brain and retinal vasculatures. In the cerebellum, the two signaling systems are substantially redundant in maintaining the BBB, with isolated loss of some components, such as the ligand Wnt7a or the coactivator Tspan12, producing little or no barrier defect but combined loss of the two components producing a large defect in barrier integrity.
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.
Author contributions: Y.W. and J.N. designed research; Y.W., C.C., and J.W. performed research; P.M.S., C.Z., and H.J.J. contributed new reagents/analytic tools; Y.W. and J.N. analyzed data; and J.N. wrote the paper.
Reviewers: C.G., Harvard University; and B.S.C., National Cancer Institute, National Institutes of Health.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1813217115/-/DCSupplemental.
Published under the PNAS license.
