TSPAN12 Regulates Retinal Vascular Development by Promoting Norrin- but Not Wnt-Induced FZD4/β-Catenin Signaling

Harald J. Junge, Stacey Yang, Jeremy B. Burton, Kim Paes, Xiao Shu, Dorothy M. French, Mike Costa, Dennis S. Rice, Weilan Ye

Research output: Contribution to journalArticlepeer-review

222 Scopus citations

Abstract

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/β-catenin but not Wnt/β-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.

Original languageEnglish (US)
Pages (from-to)299-311
Number of pages13
JournalCell
Volume139
Issue number2
DOIs
StatePublished - Oct 16 2009
Externally publishedYes

Keywords

  • DEVBIO
  • HUMDISEASE
  • SIGNALING

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