Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Department of Oncology, University of Oxford, Oxford, UK.
Stem Cells. 2020 Sep;38(9):1149-1158. doi: 10.1002/stem.3202. Epub 2020 Jun 8.
Postnatal subventricular zone (pSVZ) stem and progenitor cell proliferation is regulated by several developmental signaling pathways such as Wnt/β-catenin. However, the molecular regulation of Wnt function in the pSVZ is poorly understood. We previously showed that Wnt signaling is upregulated in an SVZ gliomagenesis in vivo model. As well, the pro-inflammatory molecule Galectin-3 (Gal-3) increases Wnt signaling in cancer cells and is expressed in the SVZ. Therefore, we asked if Gal-3 has a similar function on Wnt signaling in the pSVZ. We interrogated Wnt signaling using a signaling reporter as well as immunohistochemistry and showed that Wnt signaling predominates upstream in the pSVZ lineage but is downregulated in migrating neuroblasts. Biochemical analysis of SVZ cells, in vivo and in neurosphere stem/progenitor cells, showed that Gal-3 physically interacts with multiple forms of β-catenin, which is a major downstream regulator of Wnt signaling. Functional analyses demonstrated, in vitro and in vivo, that Gal-3 knockdown increases Wnt signaling and conversely that Gal-3 OE inhibits Wnt/β-catenin signaling in the pSVZ. This latter result suggested that Gal-3, which is consistently increased in brain injury, may decrease pSVZ proliferation. We showed that Gal-3 OE decreased proliferation without altering cell cycle re-entry and that it increased p27Kip1, a molecule which induces cell cycle exit. Our data uncover a novel regulator of Wnt signaling in the SVZ, Gal-3, which does so in a manner opposite to cancer.
产后侧脑室下区（pSVZ）干细胞和祖细胞的增殖受到多种发育信号通路的调节，如 Wnt/β-连环蛋白。然而，Wnt 在 pSVZ 中的功能的分子调节知之甚少。我们之前表明，Wnt 信号在体内 SVZ 神经胶质瘤发生模型中上调。此外，促炎分子半乳糖凝集素-3（Gal-3）增加癌细胞中的 Wnt 信号，并且在 SVZ 中表达。因此，我们询问 Gal-3 是否对 pSVZ 中的 Wnt 信号具有类似的功能。我们使用信号报告基因以及免疫组织化学检测来研究 Wnt 信号，结果表明 Wnt 信号在 pSVZ 谱系中主要在上游起作用，但在迁移的神经母细胞中下调。SVZ 细胞的生化分析、体内和神经球干细胞/祖细胞表明，Gal-3 与多种形式的β-连环蛋白物理相互作用，β-连环蛋白是 Wnt 信号的主要下游调节剂。体外和体内的功能分析表明，Gal-3 敲低增加了 Wnt 信号，相反，Gal-3 OE 抑制了 pSVZ 中的 Wnt/β-连环蛋白信号。后一种结果表明，在脑损伤中持续增加的 Gal-3 可能会降低 pSVZ 的增殖。我们表明，Gal-3 OE 减少了增殖，而不改变细胞周期再进入，并且增加了 p27Kip1，一种诱导细胞周期退出的分子。我们的数据揭示了 SVZ 中 Wnt 信号的一种新调节剂 Gal-3，它以与癌症相反的方式起作用。
