Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Development. 2020 May 27;147(10):dev189324. doi: 10.1242/dev.189324.
R-spondins are a family of secreted proteins that play important roles in embryonic development and cancer. R-spondins have been shown to modulate the Wnt pathway; however, their involvement in other developmental signaling processes have remained largely unstudied. Here, we describe a novel function of Rspo2 in FGF pathway regulation Overexpressed Rspo2 inhibited elongation of ectoderm explants and Erk1 activation in response to FGF. By contrast, the constitutively active form of Mek1 stimulated Erk1 even in the presence of Rspo2, suggesting that Rspo2 functions upstream of Mek1. The observed inhibition of FGF signaling was accompanied by the downregulation of the FGF target genes and , which mediate anterioposterior axis specification. Importantly, these target genes were upregulated in Rspo2-depleted explants. The FGF inhibitory activity was mapped to the thrombospondin type 1 region, contrasting the known function of the Furin-like domains in Wnt signaling. Further domain analysis revealed an unexpected intramolecular interaction that might control Rspo2 signaling output. We conclude that, in addition to its role in Wnt signaling, Rspo2 acts as an FGF antagonist during mesoderm formation and patterning.
R 蛋白是一类分泌蛋白，在胚胎发育和癌症中发挥重要作用。已经证明 R 蛋白可以调节 Wnt 通路；然而，它们在其他发育信号过程中的参与仍在很大程度上未被研究。在这里，我们描述了 Rspo2 在 FGF 通路调节中的一个新功能。过表达的 Rspo2 抑制了外胚层外植体的伸长和 FGF 反应中的 Erk1 激活。相比之下，即使存在 Rspo2，组成性激活的 Mek1 也能刺激 Erk1，表明 Rspo2 在 Mek1 上游发挥作用。观察到的 FGF 信号转导抑制伴随着 FGF 靶基因 和 的下调，这些基因介导前后轴的特化。重要的是，这些靶基因在 Rspo2 耗尽的外植体中上调。FGF 抑制活性被映射到血栓素样蛋白 1 区域，与已知的 Furin 样结构域在 Wnt 信号中的功能形成对比。进一步的结构域分析揭示了一个意想不到的分子内相互作用，可能控制 Rspo2 信号输出。我们得出结论，除了在 Wnt 信号中的作用外，Rspo2 在中胚层形成和模式形成过程中作为 FGF 拮抗剂发挥作用。
