Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
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.
β-连环蛋白信号通路控制着血脑屏障（BBB）和血视网膜屏障（BRB）的发育和维持，但这两个主要配体-受体系统（Norrin 和 Wnt7a/Wnt7b 系统）之间的分工和冗余程度尚未完全确定。在这里，我们对出生后 BBB 和 BRB 维持的小鼠进行了功能丧失的遗传分析，结果显示出明显的阈值和部分冗余效应。特别是，Wnt7a 和 Norrin 或 Wnt7a 和 Frizzled4（Fz4）的联合缺失会导致 BBB 出现解剖学上的局灶性缺陷，其严重程度远远超过单独缺失 Wnt7a、Norrin 或 Fz4 时的观察结果。在小脑，胶质细胞中 Wnt7a 的选择性缺失与 Norrin 的普遍缺失相结合，重现了观察到的 Wnt7a 和 Norrin 普遍缺失时的表型，这表明胶质细胞是小脑 Wnt7a 的来源。Tspan12 是 Norrin 在视网膜中的信号共激活因子，在 BBB 维持中也具有活性，但效力不如 Norrin，这与 Tspan12 增强血管内皮细胞中 Norrin 信号幅度的模型一致。最后，在 Norrin 系统部分受损的情况下，视网膜显示出 Wnt7a/Wnt7b 系统对 BRB 发育的微小贡献。总之，这些实验定义了 Norrin 和 Wnt7a/Wnt7b 系统的几个成分在中枢神经系统区域特异性合作的程度，并揭示了部分冗余配体、受体和共激活因子在维持 BBB 和 BRB 方面的程度存在显著的区域异质性。
