Department of Medical Biophysics, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
Dev Dyn. 2022 Dec;251(12):2015-2028. doi: 10.1002/dvdy.533. Epub 2022 Sep 16.
Glypicans are a family of proteoglycans that play important roles in embryonic morphogenesis. The mammalian genome contains six glypicans (GPC1 to GPC6). GPC6 and GPC4 are the pair of glypicans that show the highest degree of homology within the family. GPC6-null embryos display bone abnormalities and severely shortened intestines.
We show that GPC6-null embryos display significantly smaller stomachs, and that Hedgehog and noncanonical Wnt signaling are dysregulated in GPC6-null stomachs. Like GPC6, GPC4 is expressed by the developing stomach. However, GPC4-null embryos have normal stomachs. To investigate whether GPC6 and GPC4 display functional overlap in the developing stomach, we crossed GPC4-null mice with GPC6 conditional mutants in which the expression of this glypican is severely reduced in the stomach. Notably, we found that the compound mutants display stomachs that are smaller than those of the GPC6 conditional mutants. We also found that this functional overlap between GPC6 and GPC4 is mediated by the noncanonical Wnt pathway.
This study demonstrates that GPC6 stimulates the growth of the embryonic stomach via Wnt and Hh signaling. In addition, we uncovered a Wnt-mediated functional overlap between GPC6 and GPC4 in the developing stomach.
Glypicans 是一类蛋白聚糖，在胚胎形态发生中发挥重要作用。哺乳动物基因组包含六个 Glypicans（GPC1 到 GPC6）。GPC6 和 GPC4 是家族中同源性最高的一对 Glypicans。GPC6 缺失胚胎表现出骨骼异常和严重缩短的肠道。
我们发现 GPC6 缺失胚胎的胃明显较小，GPC6 缺失胃中的 Hedgehog 和非经典 Wnt 信号通路失调。与 GPC6 一样，GPC4 也由发育中的胃表达。然而，GPC4 缺失胚胎的胃正常。为了研究 GPC6 和 GPC4 在发育中的胃中是否存在功能重叠，我们将 GPC4 缺失小鼠与 GPC6 条件性突变体杂交，该突变体中这种糖蛋白在胃中的表达严重减少。值得注意的是，我们发现复合突变体的胃比 GPC6 条件性突变体的胃小。我们还发现 GPC6 和 GPC4 之间的这种功能重叠是由非经典 Wnt 途径介导的。
本研究表明 GPC6 通过 Wnt 和 Hh 信号刺激胚胎胃的生长。此外，我们在发育中的胃中发现了 GPC6 和 GPC4 之间的 Wnt 介导的功能重叠。
