Positive Feedback Regulation of fzd7 Expression Robustly Shapes Wnt Signaling Range in Early Heart Development
Positive Feedback Regulation of fzd7 Expression Robustly Shapes Wnt Signaling Range in Early Heart Development
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fzd7 表达的正反馈调节稳健地塑造早期心脏发育中的 Wnt 信号范围
DOI：
10.1101/2021.09.12.458649
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hoppler Stefan
中科院分区：
文献类型：
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作者：
Yamamoto Takayoshi;Kambayashi Yuta;Afouda Boni;Otsuka Yuta;Giuraniuc Claudiu;Michiue Tatsuo;Hoppler Stefan
被称为形态形成因子的分泌分子以浓度依赖的方式控制着组织的模式。然而，它仍然不清楚如何可再现的模式可以实现扩散分子，特别是当一个薄区域的模式分化。Wnt是组织心脏发育的形态因子；特别是Wnt6在非洲爪蟾的心源性中胚层上形成模式，诱导薄心包的分化。然而，目前尚不清楚Wnt6是如何塑造如此薄的组织的。在这项研究中，我们发现Wnt受体zzzzled7在未来心脏区域以Wnt依赖的方式表达，并且这种受体反馈对于形成Wnt的陡峭梯度至关重要。此外，反馈赋予了对Wnt配体产生波动的鲁棒性，并允许系统快速达到稳定状态。我们还发现Wnt拮抗剂sFRP1在Wnt源的另一侧表达，它在一种新型硫酸肝素（HS）上积累，这种富含n -乙酰基的HS高度存在于心源性中皮层外，通过限制sFRP1的扩散实现局部抑制Wnt信号传导。这两个复杂的调控系统限制了Wnt信号传导并确保了薄心包组织的可复制模式。
Secreted molecules called morphogens govern tissue patterning in a concentration-dependent manner. However, it is still unclear how reproducible patterning can be achieved with diffusing molecules, especially when patterning differentiation of a thin region. Wnt is a morphogen that organizes cardiac development; especially Wnt6 patterns the cardiogenic mesoderm to induce differentiation of a thin pericardium inXenopus. It is, however, unclear how Wnt6 can pattern such a thin tissue. In this study, we reveal that a Wnt receptor,frizzled7, is expressed in a Wnt-dependent manner in the prospective heart region, and that this receptor-feedback is essential for shaping a steep gradient of Wnt. In addition, the feedback imparts robustness against fluctuations of Wnt ligand production and allows the system to reach a steady state quickly. We also found a Wnt antagonist sFRP1, which is expressed at the opposite side of Wnt source, accumulates on a novel type of heparan sulfate (HS), N-acetyl-rich HS, which is highly presented in the outer of cardiogenic mesoderm, achieving local inhibition of Wnt signaling by restricting sFRP1 spreading. These two intricate regulatory systems restrict Wnt signaling and ensure reproducible patterning of a thin pericardium tissue.