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Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein

Nature Cell Biology volume 8, pages 329–340 (2006)Cite this article

An Erratum to this article was published on 16 April 2006

Abstract

The Bone morphogenetic protein (Bmp) signalling gradient has a major function in the formation of the dorso-ventral axis. The zebrafish ventralized mutant, ogon, encodes Secreted Frizzled (Sizzled). sizzled is ventrally expressed in a Bmp-dependent manner and is required for the suppression of Bmp signalling on the ventral side of zebrafish embryos. However, it remains unclear how Sizzled inhibits Bmp signalling and controls ventro-lateral cell fate. We found that Sizzled stabilizes Chordin, a Bmp antagonist, by binding and inhibiting the Tolloid-family metalloproteinase, Bmp1a, which cleaves and inactivates Chordin. The cysteine-rich domain of Sizzled is required for inhibition of Bmp1a activity. Loss of both Bmp1a and Tolloid-like1 (Tll1; another Tolloid-family metalloproteinase) function leads to a complete suppression and reversal of the ogon mutant phenotype. These results indicate that Sizzled represses the activities of Tolloid-family proteins, thereby creating the Chordin–Bmp activity gradient along the dorso-ventral axis. Here, we describe a previously unrecognized role for a secreted Frizzled-related protein.

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Figure 1: Sizzled cooperates with Chordin but not with other Bmp antagonists.
Figure 2: Sizzled controls the stability of Chordin.
Figure 3: Sizzled inhibits Bmp1a and Tll1.
Figure 4: The cysteine-rich domain (CRD) of Sizzled is required for dorsalization and inhibition of Bmp1a.
Figure 5: Role of Bmp1a, Tll1 and Sizzled in dorso-ventral axis formation.

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Acknowledgements

We would like to thank N. Ueno, B. Thisse, C. Thisse, M. Halpern, K. Araki, U. Strähle, and S. Fisher for providing the DNA samples; A. Yamamoto, G. Sheng, and Y. Sasai for comments on the manuscript; M. Royle for editing the manuscript; H. Akiyama, K. Bando and Y. Wataoka for fish care and technical assistance; and all members of our laboratory for valuable discussion.

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  1. Taijiro Yabe

    Present address: Department of Genetics, University of Wisconsin–Madison, Madison, WI 53706, USA

Authors and Affiliations

  1. Laboratory for Vertebrate Axis Formation, Center for Developmental Biology, RIKEN, 2–2–3 Minatojima-minamimachi, Chuo-ku Kobe, Hyogo, 650–0047, Japan

    Osamu Muraoka, Takashi Shimizu, Taijiro Yabe, Hideaki Nojima, Young-Ki Bae & Masahiko Hibi

  2. Bioscience and Biotechnology Center, Nagoya University, Nagoya, 464–8601, Aichi, Japan

    Hisashi Hashimoto

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Muraoka, O., Shimizu, T., Yabe, T. et al. Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein. Nat Cell Biol 8, 329–340 (2006). https://doi.org/10.1038/ncb1379

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