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

Alice H Reis1, Sergei Y Sokol2

  • 1Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, USA. alice.reis@mssm.edu.

Scientific Reports
|June 29, 2021
PubMed

Insights

Rspo2 acts as a Wnt antagonist during Xenopus development, inhibiting TCF3 phosphorylation to control gene activation. This Wnt signaling regulation is independent of Rspo2 binding to RNF43/ZNRF3 and LGR4/5.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • The Wnt pathway, mediated by the β-catenin-T-cell factor (TCF) complex, is crucial for embryonic development and cancer.
  • R-spondins (RSPOs) typically potentiate Wnt signaling by binding RNF43/ZNRF3 E3 ubiquitin ligases and LGR4/5 receptors, preventing Frizzled degradation.

Purpose of the Study:

  • To investigate the role of Rspo2 in Xenopus anteroposterior axis specification.
  • To elucidate the mechanism by which Rspo2 regulates Wnt signaling.

Main Methods:

  • Morphological analysis in Xenopus embryos.
  • Gene expression analysis of Wnt pathway targets.
  • Assessment of pathway mediators and protein phosphorylation.
  • Rescue experiments in TCF3-depleted embryos.

Main Results:

  • Rspo2 functions as a Wnt antagonist during Xenopus development, affecting morphology and gene targets.
  • Rspo2's Wnt inhibitory activity is independent of its binding to RNF43/ZNRF3 and LGR4/5 receptors.
  • Rspo2 does not affect Dishevelled phosphorylation in response to Wnt ligands.
  • Rspo2 inhibits Wnt signaling by suppressing TCF3/TCF7L1 phosphorylation, crucial for target gene activation.
  • Depletion of TCF3 rescues the anteriorizing effects of Rspo2.

Conclusions:

  • Rspo2 acts as a context-specific Wnt antagonist in Xenopus development.
  • The mechanism involves direct inhibition of TCF3/TCF7L1 phosphorylation, independent of canonical RSPO-mediated potentiation.
  • Rspo2 represents a novel regulator of Wnt signaling through modulation of TCF transcription factor activity.

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