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

Nat Cell Biol. 2006 Apr;8(4):329-38. doi: 10.1038/ncb1379. Epub 2006 Mar 5.

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.

MeSH terms

  • Animals
  • Body Patterning / physiology*
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Morphogenetic Proteins / metabolism
  • Cell Polarity*
  • Cysteine / chemistry
  • Cysteine / metabolism
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / metabolism
  • Gene Expression Regulation, Developmental
  • Glycoproteins / antagonists & inhibitors
  • Glycoproteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Metalloproteases / antagonists & inhibitors
  • Metalloproteases / metabolism
  • Morphogenesis / genetics
  • Oligonucleotides / pharmacology
  • Phenotype
  • Tolloid-Like Metalloproteinases
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / physiology*
  • Zebrafish* / embryology
  • Zebrafish* / genetics
  • Zebrafish* / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Oligonucleotides
  • Zebrafish Proteins
  • szl protein, zebrafish
  • chordin
  • Metalloproteases
  • Tolloid-Like Metalloproteinases
  • Cysteine