ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation
- 1 January 2020
- journal article
- research article
- Published by The Company of Biologists in Development
- Vol. 147 (17)
- https://doi.org/10.1242/dev.185678
Abstract
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.Funding Information
- National Natural Science Foundation of China (81670470)
- Shanghai Municipal Commission for Science and Technology (18411953500)
- Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-05-E00054)
- Fundamental Research Funds for the Central Universities
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