Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein |
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Authors: | Muraoka Osamu Shimizu Takashi Yabe Taijiro Nojima Hideaki Bae Young-Ki Hashimoto Hisashi Hibi Masahiko |
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Institution: | Laboratory for Vertebrate Axis Formation, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku Kobe, Hyogo 650-0047, Japan. |
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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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