TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

Maria B. Lai, Chi Zhang, Jianli Shi, Verity Johnson, Lavan Khandan, John McVey, Michael W. Klymkowsky, Zhe Chen, Harald J. Junge

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Accessory proteins in Frizzled (FZD) receptor complexes are thought to determine ligand selectivity and signaling amplitude. Genetic evidence indicates that specific combinations of accessory proteins and ligands mediate vascular β-catenin signaling in different CNS structures. In the retina, the tetraspanin TSPAN12 and the ligand norrin (NDP) mediate angiogenesis, and both genes are linked to familial exudative vitreoretinopathy (FEVR), yet the molecular function of TSPAN12 remains poorly understood. Here, we report that TSPAN12 is an essential component of the NDP receptor complex and interacts with FZD4 and NDP via its extracellular loops, consistent with an action as co-receptor that enhances FZD4 ligand selectivity for NDP. FEVR-linked mutations in TSPAN12 prevent the incorporation of TSPAN12 into the NDP receptor complex. In vitro and in Xenopus embryos, TSPAN12 alleviates defects of FZD4 M105V, a mutation that destabilizes the NDP/FZD4 interaction. This study sheds light on the poorly understood function of accessory proteins in FZD signaling.

Original languageEnglish (US)
Pages (from-to)2809-2822
Number of pages14
JournalCell reports
Volume19
Issue number13
DOIs
StatePublished - Jun 27 2017
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank Davide Proverbio and Teodor Aastrup at Attana Research Services and Systems and Jana Valnohova and Gunnar Schulte at Karolinska Institutet for sharing unpublished data on the application of Quartz Crystal Microbalance technology to study ligand receptor interactions. We would also like to thank Dr. Paul Muhlrad for providing critical comments on the manuscript. This work was supported by ACS IRG #57-001-53 from the American Cancer Society (to H.J.J.), a Boettcher Foundation Webb-Waring Biomedical Research Award (to H.J.J.), a grant from the NIH (R01EY024261 to H.J.J.), and the Linda Crnic Institute (to M.W.K.).

Publisher Copyright:
© 2017 The Author(s)

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • FEVR
  • FZD4
  • NDP
  • Norrin
  • TSPAN12
  • angiogenesis
  • blood-brain barrier
  • blood-retina barrier
  • retina
  • tetraspanin

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