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XB-ART-58233
Sci Rep January 1, 2021; 11 (1): 13433.

Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification.

Reis AH , Sokol SY .


Abstract
The Wnt pathway activates target genes by controlling the β-catenin-T-cell factor (TCF) transcriptional complex during embryonic development and cancer. This pathway can be potentiated by R-spondins, a family of proteins that bind RNF43/ZNRF3 E3 ubiquitin ligases and LGR4/5 receptors to prevent Frizzled degradation. Here we demonstrate that, during Xenopus anteroposterior axis specification, Rspo2 functions as a Wnt antagonist, both morphologically and at the level of gene targets and pathway mediators. Unexpectedly, the binding to RNF43/ZNRF3 and LGR4/5 was not required for the Wnt inhibitory activity. Moreover, Rspo2 did not influence Dishevelled phosphorylation in response to Wnt ligands, suggesting that Frizzled activity is not affected. Further analysis indicated that the Wnt antagonism is due to the inhibitory effect of Rspo2 on TCF3/TCF7L1 phosphorylation that normally leads to target gene activation. Consistent with this mechanism, Rspo2 anteriorizing activity has been rescued in TCF3-depleted embryos. These observations suggest that Rspo2 is a context-specific regulator of TCF3 phosphorylation and Wnt signaling.

PubMed ID: 34183732
PMC ID: PMC8239024
Article link: Sci Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ag1 axin2 cdx4 foxg1 fzd1 krt12.4 lgr4 lgr5 msgn1 myod1 otx2 rnf43 rspo2 tcf3 tcf7l1 wnt3a wnt5a wnt8a znrf3
GO keywords: Wnt signaling pathway involved in animal/vegetal axis specification
Morpholinos: rspo2 MO5 tcf7l1 MO1


Article Images: [+] show captions