Erk and MAPK signaling is essential for intestinal development through Wnt pathway modulation
| Autor: | Kewen Hu, Heng-Yu Fan, Liang Li, Gaigai Wei, Lingling Fan, Jiwei Chen, Hans Clevers, Guojiu Fang, Zhiyang Zeng, Dali Li, Xueli Zhang, Ganglong Gao, Xiufeng Pang, Mingyao Liu, Na Gao |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Indian hedgehog MAP Kinase Signaling System Bone Morphogenetic Protein 4 03 medical and health sciences Mice 0302 clinical medicine Mesenchymal cell proliferation Animals Molecular Biology Protein kinase B Wnt Signaling Pathway PI3K/AKT/mTOR pathway 030304 developmental biology Mice Knockout Mitogen-Activated Protein Kinase 1 0303 health sciences Mitogen-Activated Protein Kinase 3 biology TOR Serine-Threonine Kinases Wnt signaling pathway biology.organism_classification Hedgehog signaling pathway Cell biology Intestines 030220 oncology & carcinogenesis raf Kinases Stem cell Proto-Oncogene Proteins c-akt Developmental Biology |
| Zdroj: | Development (Cambridge), 147(17). Company of Biologists Ltd |
| ISSN: | 0950-1991 |
| Popis: | Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here, we have found that deletion of Erk1 and Erk2 (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 feedback regulation, leading to Ras/Raf cascade activation that transactivated Akt activity to stimulate the mTor and Wnt/β-catenin pathways. Moreover, Erk1/2 deficiency reduced the levels of Indian hedgehog 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 the lifespan of mutant mice. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development. |
| Databáze: | OpenAIRE |
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