Secreted frizzled-related protein 2 (sFRP2) redirects non-canonical Wnt signaling from Fz7 to Ror2 during vertebrate gastrulation

Convergent extension (CE) movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a/Ror2 complexes at the membrane, while it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain (CRD) of sFRP2 is sufficient for Ror2 activation and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their CRDs also promotes Ror2 mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.