Glypican-6 and Glypican-4 stimulate embryonic stomach growth by regulating Hedgehog and noncanonical Wnt signaling.

BACKGROUND

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.

RESULTS

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.

CONCLUSION

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.