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Cell Commun Signal November 19, 2013; 11 89.
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A secreted splice variant of the Xenopus frizzled-4 receptor is a biphasic modulator of Wnt signalling.

Gorny AK , Kaufmann LT , Swain RK , Steinbeisser H .

BACKGROUND: Activation of the Wnt signalling cascade is primarily based on the interplay between Wnt ligands, their receptors and extracellular modulators. One prominent family of extracellular modulators is represented by the SFRP (secreted Frizzled-related protein) family. These proteins have significant similarity to the extracellular domain of Frizzled receptors, suggesting that they bind Wnt ligands and inhibit signalling. The SFRP-type protein Fz4-v1, a splice variant of the Frizzled-4 receptor found in humans and Xenopus, was shown to augment Wnt/β-catenin signalling, and also interacts with those Wnt ligands that act on β-catenin-independent Wnt pathways. FINDINGS: Here we show that Xenopus Fz4-v1 can activate and inhibit the β-catenin-dependent Wnt pathway. Gain-of-function experiments revealed that high Wnt/β-catenin activity is inhibited by low and high concentrations of Fz4-v1. In contrast, signals generated by low amounts of Wnt ligands were enhanced by low concentrations of Fz4-v1 but were repressed by high concentrations. This biphasic activity of Fz4-v1 was not observed in non-canonical Wnt signalling. Fz4-v1 enhanced β-catenin-independent Wnt signalling triggered by either low or high doses of Wnt11. Antisense morpholino-mediated knock-down experiments demonstrated that in early Xenopus embryos Fz4-v1 is required for the migration of cranial neural crest cells and for the development of the dorsal fin. CONCLUSIONS: For the first time, we show that a splice variant of the Frizzled-4 receptor modulates Wnt signalling in a dose-dependent, biphasic manner. These results also demonstrate that the cystein-rich domain (CRD), which is shared by Fz4-v1 and SFRPs, is sufficient for the biphasic activity of these secreted Wnt modulators.

PubMed ID: 24252524
PMC ID: PMC4077065
Article link: Cell Commun Signal

Species referenced: Xenopus laevis
Genes referenced: ctnnb1 fzd4 mapk8 sox10 twist1 wnt11 wnt3a wnt8b
Morpholinos: Fzd4 MO1

Article Images: [+] show captions
References [+] :
Bovolenta, Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. 2008, Pubmed