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

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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Correspondence to Masahiko Hibi.

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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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