Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein
Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein
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DOI：
10.1038/ncb1379
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发表时间：
2006-04-01
影响因子：
21.3
通讯作者：
Hibi, M
中科院分区：
文献类型：
--
作者：
Muraoka, O;Shimizu, T;Hibi, M
骨形态发生蛋白(BMP)信号梯度在背腹轴的形成中起着重要作用。斑马鱼的腹腔化突变体ogon编码分泌的Frizzed(Sizzed)。Sizzed以BMP依赖的方式在腹侧表达，是抑制斑马鱼胚胎腹侧BMP信号所必需的。然而，目前尚不清楚sizzleed如何抑制BMP信号转导和控制腹侧细胞命运。我们发现，sizzed通过结合和抑制Tolloid家族金属蛋白酶Bmp1a来稳定BMP拮抗剂Chordin，Bmp1a可以裂解和失活Chordin。SIZZLED的富含半胱氨酸的结构域是抑制Bmp1a活性所必需的。Bmp1a和Tolloid-like 1(TLL1；另一种Tolloid家族金属蛋白酶)功能的丧失导致ogon突变表型的完全抑制和逆转。这些结果表明，sizzed抑制了Tolloid家族蛋白的活性，从而产生了沿背腹轴的Chordin-BMP活性梯度。在这里，我们描述了一种分泌的Frizzled相关蛋白以前未被认识到的作用。
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.