Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Matrix Biol. 2020 Jun;88:19-32. doi: 10.1016/j.matbio.2019.11.002. Epub 2019 Nov 20.
We report here that Glypican-6 (GPC6)-null mice display at birth small intestines that are 75% shorter than those of normal littermates. Notably, we demonstrate that the role of GPC6 in intestinal elongation is mediated by both Hedgehog (Hh) and non-canonical Wnt signaling. Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. Here we provide strong support to this hypothesis by showing that GPC6 binds to Ptc1 in the mesenchymal layer of embryonic intestines. This study also provides experimental evidence that strongly suggests that GPC6 inhibits the activity of Wnt5a on the intestinal epithelium by binding to this growth factor, and reducing its release from the surrounding mesenchymal cells. Finally, we show that whereas the mesenchymal layer of GPC6-null intestines displays reduced cell proliferation and a thinner smooth muscle layer, epithelial cell differentiation is not altered in the mutant gut.
我们在此报告 Glypican-6 (GPC6)-基因敲除小鼠在出生时的小肠长度比正常同窝仔鼠短 75%。值得注意的是，我们证明了 GPC6 在肠伸长中的作用是通过 Hedgehog (Hh) 和非经典 Wnt 信号通路介导的。基于体外实验的结果，我们之前曾提出 GPC6 通过与 Hh 和 Patched1 (Ptc1) 相互作用，并促进/稳定它们的相互作用来刺激 Hh 信号通路。在这里，我们通过显示 GPC6 在胚胎肠的间充质层中与 Ptc1 结合，为这一假设提供了有力的支持。这项研究还提供了实验证据，强烈表明 GPC6 通过与生长因子结合并减少其从周围间充质细胞中的释放来抑制 Wnt5a 在肠上皮细胞上的活性。最后，我们发现 GPC6 基因敲除鼠的间充质层显示出细胞增殖减少和平滑肌层变薄，而突变肠道中的上皮细胞分化没有改变。
