Abstract
Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the 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, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains 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.
Highlights
Wnt signaling plays a crucial role in embryogenesis as well as in adult stem cell regulation and cancer
Gain and Loss of sFRP2 Impairs CE Movements in Xenopus— sFRP2 is expressed in the dorsal mesoderm of a gastrulating embryo [39], and its expression pattern overlaps with several non-canonical Wnt pathway components, including Wnt11, Wnt5a [31], Frizzled 7 (Fz7), Fz8 [40, 41], and receptor 2 (Ror2) [18]
Co-expression of Ror2 and Fz7 Leads to Mutually Exclusive Wnt Pathway Activation—A tight regulation of the different Wnt signaling cascades is crucial for proper cell migration during embryonic development
Summary
Wnt signaling plays a crucial role in embryogenesis as well as in adult stem cell regulation and cancer. We demonstrate that, in zebrafish embryos, sFRP2 and Ror2 prevent the internalization of Fz7 upon Wnt5a stimulation, suggesting repression of Fz7-mediated non-canonical signaling by blocking its endocytosis. Knockdown of sFRP1 and frzb2 reduced the expression of papc compared with control embryos, suggesting that sFRP1 and frzb2 positively modulate Ror2 signaling (Fig. 4A).
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