Robust stability of the embryonic axial pattern requires a secreted scaffold for chordin degradation
Robust stability of the embryonic axial pattern requires a secreted scaffold for chordin degradation
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DOI：
10.1016/j.cell.2008.07.008
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发表时间：
2008-09-05
期刊：
影响因子：
64.5
通讯作者：
Sasai, Yoshiki
中科院分区：
文献类型：
--
作者：
Inomata, Hidehiko;Haraguchi, Tomoko;Sasai, Yoshiki
脊椎动物胚胎发生过程中的背轴形成表现出强大的抗干扰图案信号。然而，如何在分子水平上支持这种稳定性在很大程度上仍然难以捉摸。在这里，我们表明，非洲爪蟾ONT 1，嗅觉调节素类分泌蛋白，稳定轴的形成，限制脊索蛋白的活动在背侧。当ONT 1功能减弱时，正常亚有效剂量的Chordin使胚胎变得过度背侧化。ONT 1通过不同的结构域结合Chordin和BMP 1/Tolloid类蛋白酶（B1 TP），并作为分泌的支架，通过促进酶-底物结合来增强B1 TP介导的Chordin降解。ONT 1对于轴向组织中的BMP信号传导的微调是不可或缺的，并且已经提出了对于背侧表达的BMP（如Abladium）的类似作用。同时抑制ONT 1和背侧表达的BMP（AAP 4和BMP 2）协同引起剧烈的背侧化。这些结果表明，稳定的轴形成依赖于两个补偿调节途径，涉及ONT 1/B1 TP和背侧表达的BMP。
Dorsal axial formation during vertebrate embryogenesis exhibits robust resistance to perturbations in patterning signals. However, how such stability is supported at the molecular level remains largely elusive. Here we show that Xenopus ONT1, an Olfactomedin-class secreted protein, stabilizes axial formation by restricting Chordin activity on the dorsal side. When ONT1 function is attenuated, the embryo becomes hyperdorsalized by a normally subeffective dose of Chordin. ONT1 binds Chordin and BMP1/Tolloid-class proteinases (B1TP) via distinct domains and acts as a secreted scaffold that enhances B1TP-mediated Chordin degradation by facilitating enzyme-substrate association. ONT1 is indispensable for fine-tuning BMP signaling in the axial tissue, and a similar role has been suggested for dorsally expressed BMPs such as ADMP. Simultaneous inhibition of ONT1 and dorsally expressed BMPs (ADMP and BMP2) synergistically caused drastic dorsalization. These results indicate that stable axial formation depends on two compensatory regulatory pathways involving ONT1/B1TP and dorsally expressed BMPs.