Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75^NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development.

中文翻译：

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Nradd 作为 Wnt/β-Catenin 信号传导的负反馈调节剂并促进细胞凋亡


Wnt/β-连环蛋白信号传导控制许多生物过程，以在发育和稳态过程中产生和维持适当的组织大小、组织和功能。因此，Wnt 通路成分和调节剂的突变会导致疾病，包括遗传性疾病和癌症。通路相关疾病的靶向治疗需要详细了解微调 Wnt 信号传导的调节机制。在这里，我们确定了神经营养蛋白受体相关死亡结构域 (Nradd)，p75 神经营养蛋白受体 (p75 ^NTR ) 的同源物，作为斑马鱼胚胎和哺乳动物细胞中 Wnt/β-连环蛋白信号传导的负调节因子。 Nradd 显着抑制斑马鱼原肠胚形成过程中 Wnt8 介导的中胚层和神经外胚层模式。 Nradd 位于质膜上，与 Wnt 受体复合物发生物理相互作用，并与 Wnt/β-连环蛋白信号传导协同增强细胞凋亡。我们的功能分析表明，N-糖基化的 N 末端和含有死亡结构域的 C 末端区域对于抑制 Wnt 信号传导和细胞凋亡都是必需的。最后，Nradd 可以诱导哺乳动物细胞凋亡。因此，Nradd 作为发育过程中 Wnt/β-连环蛋白信号传导的调节剂来调节细胞死亡。