ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation

Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here we found that deletion of Erk1/2 in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of the feedback regulation leading to Ras/Raf cascade activation which transactivated Akt activity to stimulate the mTor and Wnt/β-catenin pathways. Moreover, Erk1/2 deficiency reduced the Indian hedgehog level and the expression of downstream pathway components including mesenchymal Bmp4, a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged mutant mice life span. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development.