Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein.
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.
Muraoka
Osamu
O
Laboratory for Vertebrate Axis Formation, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku Kobe, Hyogo 650-0047, Japan.
Shimizu
Takashi
T
Yabe
Taijiro
T
Nojima
Hideaki
H
Bae
Young-Ki
YK
Hashimoto
Hisashi
H
Hibi
Masahiko
M
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016764:Cell Polarity; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009024:Morphogenesis / Q000235:genetics; D009841:Oligonucleotides / Q000494:pharmacology; D010641:Phenotype; D055394:Tolloid-Like Metalloproteinases; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
D019485:Bone Morphogenetic Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009841:Oligonucleotides; D029961:Zebrafish Proteins; C491672:szl protein, zebrafish; C054234:chordin; D045726:Metalloproteases; D055394:Tolloid-Like Metalloproteinases; D003545:Cysteine