State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Wuhan, China.
College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China.
PLoS Biol. 2020 Jul 23;18(7):e3000561. doi: 10.1371/journal.pbio.3000561. eCollection 2020 Jul.
Maternal β-catenin activity is essential and critical for dorsal induction and its dorsal activation has been thoroughly studied. However, how the maternal β-catenin activity is suppressed in the nondorsal cells remains poorly understood. Nanog is known to play a central role for maintenance of the pluripotency and maternal -zygotic transition (MZT). Here, we reveal a novel role of Nanog as a strong repressor of maternal β-catenin signaling to safeguard the embryo against hyperactivation of maternal β-catenin activity and hyperdorsalization. In zebrafish, knockdown of nanog at different levels led to either posteriorization or dorsalization, mimicking zygotic or maternal activation of Wnt/β-catenin activities, and the maternal zygotic mutant of nanog (MZnanog) showed strong activation of maternal β-catenin activity and hyperdorsalization. Although a constitutive activator-type Nanog (Vp16-Nanog, lacking the N terminal) perfectly rescued the MZT defects of MZnanog, it did not rescue the phenotypes resulting from β-catenin signaling activation. Mechanistically, the N terminal of Nanog directly interacts with T-cell factor (TCF) and interferes with the binding of β-catenin to TCF, thereby attenuating the transcriptional activity of β-catenin. Therefore, our study establishes a novel role for Nanog in repressing maternal β-catenin activity and demonstrates a transcriptional switch between β-catenin/TCF and Nanog/TCF complexes, which safeguards the embryo from global activation of maternal β-catenin activity.
母源β-连环蛋白活性对于背侧诱导是必需且关键的，其背侧激活已被深入研究。然而，母源β-连环蛋白活性在非背侧细胞中是如何被抑制的仍知之甚少。Nanog 已知在维持多能性和母源-合子过渡（MZT）中发挥核心作用。在这里，我们揭示了 Nanog 的一个新角色，即作为母源β-连环蛋白信号的强烈抑制剂，以保护胚胎免受母源β-连环蛋白活性的过度激活和过度背侧化。在斑马鱼中，nanog 在不同水平的敲低导致后部化或背侧化，模拟合子或母源 Wnt/β-连环蛋白活性的激活，而 nanog 的母源合子突变体（MZnanog）显示出母源β-连环蛋白活性的强烈激活和过度背侧化。尽管组成型激活型 Nanog（缺乏 N 端的 Vp16-Nanog）可以完全挽救 MZnanog 的 MZT 缺陷，但它不能挽救由β-连环蛋白信号激活引起的表型。从机制上讲，Nanog 的 N 端直接与 T 细胞因子（TCF）相互作用，并干扰β-连环蛋白与 TCF 的结合，从而减弱β-连环蛋白的转录活性。因此，我们的研究确立了 Nanog 在抑制母源β-连环蛋白活性中的新作用，并证明了β-连环蛋白/TCF 和 Nanog/TCF 复合物之间的转录开关，从而保护胚胎免受母源β-连环蛋白活性的全局激活。
