Nkd1 functions as a passive antagonist of Wnt signaling.
Nkd1 functions as a passive antagonist of Wnt signaling.
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DOI：
10.1371/journal.pone.0074666
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Van Raay TJ
中科院分区：
文献类型：
--
作者：
Angonin D;Van Raay TJ
WNT信号参与干细胞发育和动态平衡的许多方面。事实上，Wnt信号的错误调控与许多疾病，特别是结直肠癌有关，这一事实突显了它的重要性。然而，Wnt信号如何自我调节还不是很清楚。有几个Wnt负反馈调节因子，它们是Wnt信号的主动拮抗剂，但其中一个反馈调节因子Nkd1与其他拮抗剂相比活性降低，但仍然是一个负反馈调节因子。在这里，我们描述了我们使用Wnt信号来了解Nkd1在斑马鱼突变系中的作用的努力。在其中几个品系中，Nkd1的功能并不比野生型胚胎更活跃。然而，我们发现在Wnt/平面细胞极性突变体Silberblick(SLb/wnt11)和三叶虫(tri/Vang12)中，Nkd1‘S拮抗典型的Wnt/β-catenin信号转导的能力增强。虽然SLB和TRI突变体在典型的Wnt信号中没有表现出变化，但我们发现它们对此高度敏感。在SLb或Tri突变体中过表达规范的Wnt/β-catenin配体Wnt8a导致胚胎背化，其中Tri突变体对Wnt8a比SLb突变体更敏感。此外，Nkd1可以挽救由Wnt8a引起的TRI的过度背侧化。这些结果表明，Nkd1作为Wnt信号的被动拮抗剂发挥作用，只有当Wnt信号的动态平衡水平被打破或Wnt信号变得不稳定时才起作用。
Wnt signaling is involved in many aspects of development and in the homeostasis of stem cells. Its importance is underscored by the fact that misregulation of Wnt signaling has been implicated in numerous diseases, especially colorectal cancer. However, how Wnt signaling regulates itself is not well understood. There are several Wnt negative feedback regulators, which are active antagonists of Wnt signaling, but one feedback regulator, Nkd1, has reduced activity compared to other antagonists, yet is still a negative feedback regulator. Here we describe our efforts to understand the role of Nkd1 using Wnt signaling compromised zebrafish mutant lines. In several of these lines, Nkd1 function was not any more active than it was in wild type embryos. However, we found that Nkd1’s ability to antagonize canonical Wnt/β-catenin signaling was enhanced in the Wnt/Planar Cell Polarity mutants silberblick (slb/wnt11) and trilobite (tri/vangl2). While slb and tri mutants do not display alterations in canonical Wnt signaling, we found that they are hypersensitive to it. Overexpression of the canonical Wnt/β-catenin ligand Wnt8a in slb or tri mutants resulted in dorsalized embryos, with tri mutants being much more sensitive to Wnt8a than slb mutants. Furthermore, the hyperdorsalization caused by Wnt8a in tri could be rescued by Nkd1. These results suggest that Nkd1 functions as a passive antagonist of Wnt signaling, functioning only when homeostatic levels of Wnt signaling have been breached or when Wnt signaling becomes destabilized.
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DOI：
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发表时间：
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影响因子：
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DOI：
10.1073/pnas.1013170108
发表时间：
2011-02-08
影响因子：
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作者：
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