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.
ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation
These authors contributed equally to this work
Currently Viewing Accepted Manuscript - Newer Version Available
Gaigai Wei, Na Gao, Jiwei Chen, Lingling Fan, Zhiyang Zeng, Ganglong Gao, Liang Li, Guojiu Fang, Kewen Hu, Xiufeng Pang, Heng-Yu Fan, Hans Clevers, Mingyao Liu, Xueli Zhang, Dali Li; ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation. Development 2020; dev.185678. doi: https://doi.org/10.1242/dev.185678
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