Ogon/Secreted Frizzled functions as a negative feedback regulator of Bmp signaling

Abstract

The zebrafish mutant ogon (also called mercedes and short tail) displays ventralized phenotypes similar to the chordino (dino) mutant, in which the gene for the Bmp antagonist Chordin is mutated. We isolated the gene responsible for ogon by a positional cloning strategy and found that the ogon locus encodes a zebrafish homolog of Secreted Frizzled(Sizzled), which has sequence similarity to a Wnt receptor, Frizzled. Unlike other secreted Frizzled-related proteins (sFrps) and the Wnt inhibitor Dickkopf1, the misexpression of Ogon/Sizzled dorsalized, but did not anteriorize, the embryos, suggesting a role for Ogon/Sizzled in Bmp inhibition. Ogon/Sizzled did not inhibit a Wnt8-dependent transcription in the zebrafish embryo. ogon/sizzled was expressed on the ventral side from the late blastula through the gastrula stages. The ventral ogon/sizzled expression in the gastrula stage was reduced or absent in the swirl/bmp2b mutants but expanded in the chordinomutants. Misexpression of ogon/sizzled did not dorsalize the chordino mutants, suggesting that Ogon/Sizzled required Chordin protein for dorsalization and Bmp inhibition. These data indicate that Ogon/Sizzled functions as a negative regulator of Bmp signaling and reveal a novel role for a sFrp in dorsoventral patterning.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…Noggin, follistatin, and chordin, the first neural inducers that were identified (Hemmati-Brivanlou et al 1994;Sasai et al 1994Sasai et al , 1995, act by suppressing BMP signaling (Piccolo et al 1996;Zimmerman et al 1996;Fainsod et al 1997). Additional BMP antagonists secreted from the organizer include Cerberus, Gremlin, Dan, Drm, Coco, and Ogon/Sizzled (sFRP) (Wagner and Mullins 2002;Yabe et al 2003).…”

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

“…Sizzled, a secreted frizzled-related protein (sFRP) originally described as a Wnt signaling antagonist, has surprisingly been identified as the product of the ogon/mercedes locus, that acts as an inhibitor of BMP signaling in zebrafish dorsal-ventral patterning (Martyn and SchulteMerker, 2003;Yabe et al, 2003). It has recently been shown that Xenopus and zebrafish Sizzled can act by binding BMP1/TLD-like proteinases and inhibiting their chordinase activity (Lee et al, 2006) (Fig.…”

A direct role for Wnt8 in ventrolateral mesoderm patterning

“…1B), consistent with the suggestion that wnt8 loss-of-function embryos do not provide a BMP-permissive environment. szl encodes a feedback inhibitor of BMP, thus its expression is a readout of BMP signaling activity (Martyn and Schulte-Merker, 2003;Yabe et al, 2003). szl is expressed in the ventral embryo before and during gastrulation and in the tailbud and ventral posterior epidermis at bud stage (Yabe et al, 2003).…”