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Cell Rep
2017 Jun 27;1913:2809-2822. doi: 10.1016/j.celrep.2017.06.004.
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TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling.
Lai MB, Zhang C, Shi J, Johnson V, Khandan L, McVey J, Klymkowsky MW, Chen Z, Junge HJ.
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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.
Figure 7.
TSPAN12 Enhances NDP-Induced Axis Duplication in Frog Embryos
(A) Anterior-posterior axis in stage 18 control Xenopus laevis embryo revealed by in situ hybridization with a sox3 probe.
(B) Axis duplication induced by hNDP and hFZD4 RNA co-injection.
(C) 44–58 embryos per group were analyzed. Two independent experiments showed very similar results. Co-injection of hTSPAN12 RNA increases the incidence of axis duplication in hFZD4- and hFZD4 M105V-expressing embryos.
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