Positive feedback regulation of fzd7 expression robustly shapes a steep Wnt gradient in Xenopus heart development, together with sFRP1 and heparan sulfate

Takayoshi Yamamoto* (Corresponding Author), Yuta Kambayashi, Yuta Otsuka, Boni Afouda, Vasile Giuraniuc, Tatsuo Michiue, Stefan Hoppler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Secreted molecules called morphogens govern tissue patterning in a concentration-dependent manner. However, it is still unclear how reproducible patterning can be achieved with diffusing molecules, especially when that patterning concerns differentiation of thin tissues. Wnt is a morphogen that organizes cardiac development. Wnt6 patterns cardiogenic mesoderm to induce
differentiation of a thin tissue, the pericardium, in Xenopus. In this study, we revealed that a Wnt receptor, frizzled7, is expressed in a Wnt-dependent manner. With a combination of experiments and mathematical modeling, this receptor-feedback appears essential to shape a steep gradient of Wnt signaling. In addition, computer simulation revealed that this feedback imparts robustness
against variations of Wnt ligand production and allows the system to reach a steady state quickly. We also found that a Wnt antagonist sFRP1, which is expressed on the opposite side of the Wnt source, accumulates on N-acetyl-rich heparan sulfate (HS). N-acetyl-rich HS concentration is high between the sources of Wnt and sFRP1, achieving local inhibition of Wnt signaling via restriction of sFRP1 spreading. These integrated regulatory systems restrict the Wnt signaling
range and ensure reproducible patterning of the thin pericardium.
Original languageEnglish
Article number73818
Number of pages21
Publication statusPublished - 9 Aug 2022

Bibliographical note

We thank Dr. Yukio Nakamura (Aberdeen University, UK; Present address: Repertoire Genesis Inc., Japan.) and Dr. Masanori Taira (Chuo University, Japan) for their help in initiating this project; Dr. Takehiko Nakamura (Seikagaku Corporation, Japan) for NAH46 antibody and hybridoma; Dr. Osamu Yoshie (Kindai University, Japan) for HepSS-1 hybridoma; Dr. Makoto Matsuyama (Shigei Medical Research Institute, Japan) for the contribution to the generation of
NAH46 and HepSS-1 antibody from the hybridomas; Dr. Steven D. Aird for technical editing of the manuscript. This international collaboration was supported in part by Daiwa Anglo-Japanese Foundation (12969/13787 to T.Y., B.A., T.M., and S.H.); with additional research support in Japan from MEXT/JSPS KAKENHI (19K16138 to T.Y., 18K06244/21K06183 to T.Y. and T.M.); and in the United Kingdom from BHF (RG/18/8/33673 to S.H.) and BBSRC (BB/N021924/1; BB/M001695/1 to S.H.). S.H. was a Royal Society/Leverhulme Trust Senior
Research Fellow (SRF\R1\191017).


  • Wnt signal
  • Frizzled
  • Heart
  • Gene Regulatory Circuit
  • Morphogen
  • xenopus


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