Zebrafish foxo3b negatively regulates canonical Wnt signaling to affect early embryogenesis.
Zebrafish foxo3b negatively regulates canonical Wnt signaling to affect early embryogenesis.
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斑马鱼foxo3b负调控经典Wnt信号传导影响早期胚胎发生
DOI：
10.1371/journal.pone.0024469
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Xiao W
中科院分区：
文献类型：
--
作者：
Xie XW;Liu JX;Hu B;Xiao W
FOXO基因通过调节细胞凋亡、增殖和氧化应激控制，参与了血管发育和稳态的许多方面。此外，FOXO基因已被证明通过与T细胞因子竞争结合β-catenin来抑制Wnt/β-catenin信号。然而，这种抑制在体内，特别是在胚胎发生中的重要性仍然未知。阐明FOXO基因在胚胎发生中的作用将有助于我们进一步了解其相关的生理功能。斑马鱼foxo3b基因是哺乳动物FOXO3的同源基因，在母体中表达，在胚胎早期普遍分布，后来局限于大脑。在morpholino介导的foxo3b基因敲低后，斑马鱼胚胎出现轴和神经外胚层形成缺陷，提示其在早期胚胎发生中起关键作用。胚胎发育不同阶段的标记基因染色、表型分析和挽救实验表明，foxo3b通过负调控母代和受精卵Wnt/β-catenin信号通路发挥作用。此外，我们在体外和体内均发现foxo3b可与斑马鱼β-catenin1和β-catenin2相互作用，抑制它们的转激活，进一步证实其作用与抑制Wnt/β-catenin信号传导有关。综上所述，我们发现foxo3b在胚胎发生中发挥了非常重要的作用，并通过直接与β-catenin1和β-catenin2相互作用负调控母源和合子Wnt/β-catenin信号传导。我们的研究为FOXO转录因子在胚胎发生中的作用提供了一个体内模型。
FOXO genes are involved in many aspects of development and vascular homeostasis by regulating cell apoptosis, proliferation, and the control of oxidative stress. In addition, FOXO genes have been showed to inhibit Wnt/β-catenin signaling by competing with T cell factor to bind to β-catenin. However, how important of this inhibition in vivo, particularly in embryogenesis is still unknown. To demonstrate the roles of FOXO genes in embryogenesis will help us to further understand their relevant physiological functions. Zebrafish foxo3b gene, an orthologue of mammalian FOXO3, was expressed maternally and distributed ubiquitously during early embryogenesis and later restricted to brain. After morpholino-mediated knockdown of foxo3b, the zebrafish embryos exhibited defects in axis and neuroectoderm formation, suggesting its critical role in early embryogenesis. The embryo-developmental marker gene staining at different stages, phenotype analysis and rescue assays revealed that foxo3b acted its role through negatively regulating both maternal and zygotic Wnt/β-catenin signaling. Moreover, we found that foxo3b could interact with zebrafish β-catenin1 and β-catenin2 to suppress their transactivation in vitro and in vivo, further confirming its role relevant to the inhibition of Wnt/β-catenin signaling. Taken together, we revealed that foxo3b played a very important role in embryogenesis and negatively regulated maternal and zygotic Wnt/β-catenin signaling by directly interacting with both β-catenin1 and β-catenin2. Our studies provide an in vivo model for illustrating function of FOXO transcription factors in embryogenesis.
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