TSPAN12 Regulates Retinal Vascular Development by Promoting Norrin- but Not Wnt-Induced FZD4/β-Catenin Signaling
TSPAN12 Regulates Retinal Vascular Development by Promoting Norrin- but Not Wnt-Induced FZD4/β-Catenin Signaling
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DOI：
10.1016/j.cell.2009.07.048
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发表时间：
2009-10-16
期刊：
影响因子：
64.5
通讯作者：
Ye, Weilan
中科院分区：
文献类型：
--
作者：
Junge, Harald J.;Yang, Stacey;Ye, Weilan
编码Wnt受体Frizzled-4（FZD 4）、辅助受体LRP 5或配体Norrin的基因突变会破坏视网膜血管发育并导致眼科疾病。虽然Norrin在结构上与Wnt无关，但它结合FZD 4并激活经典Wnt途径。在这里，我们表明四跨膜蛋白Tspan 12在视网膜血管中表达，并且在Fzd 4、Lrp 5和Norrin突变小鼠中观察到Tspan 12表型缺陷的缺失。此外，Tspan 12在遗传上与Norrin或Lrp 5相互作用。过表达的TSPAN 12与Norrin受体复合物相关，并显著增加Norrin/β-连环蛋白信号传导，但不增加Wnt/β-连环蛋白信号传导，而Tspan 12 siRNA消除视网膜内皮细胞中对Norrin的转录应答，但不消除Wnt 3A。由Norrin或FZD 4突变引起的信号传导缺陷被预测为损害受体多聚化，其通过TSPAN 12的过表达而被拯救。我们的数据表明，Norrin多聚体和TSPAN 12协同促进FZD 4及其相关蛋白的多聚化，以引发生理水平的信号传导。
Mutations in the genes encoding the Wnt receptor Frizzled-4 (FZD4), coreceptor LRP5, or the ligand Norrin disrupt retinal vascular development and cause ophthalmic diseases. Although Norrin is structurally unrelated to Wnts, it binds FZD4 and activates the canonical Wnt pathway. Here we show that the tetraspanin Tspan12 is expressed in the retinal vasculature, and loss of Tspan12 phenocopies defects seen in Fzd4, Lrp5, and Norrin mutant mice. In addition, Tspan12 genetically interacts with Norrin or Lrp5. Overexpressed TSPAN12 associates with the Norrin-receptor complex and significantly increases Norrin/beta-catenin but not Wnt/beta-catenin signaling, whereas Tspan12 siRNA abolishes transcriptional responses to Norrin but not Wnt3A in retinal endothelial cells. Signaling defects caused by Norrin or FZD4 mutations that are predicted to impair receptor multimerization are rescued by overexpression of TSPAN12. Our data indicate that Norrin multimers and TSPAN12 cooperatively promote multimerization of FZD4 and its associated proteins to elicit physiological levels of signaling.