BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling
Top Cited Papers
- 19 September 2004
- journal article
- research article
- Published by Springer Nature in Nature Genetics
- Vol. 36 (10) , 1117-1121
- https://doi.org/10.1038/ng1430
Abstract
In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome1, juvenile intestinal polyposis2 and Cowden disease3, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways4,5. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase–Akt, mediates the convergence of the BMP and Wnt pathways on control of β-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.Keywords
This publication has 30 references indexed in Scilit:
- De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse IntestineScience, 2004
- Live and let die in the intestinal epitheliumCurrent Opinion in Cell Biology, 2003
- From developmental disorder to heritable cancer: it's all in the BMP/TGF-β familyNature Reviews Genetics, 2003
- BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levelsHuman Molecular Genetics, 2003
- Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposisNature Genetics, 2001
- Signaling of transforming growth factor‐β family members through Smad proteinsEuropean Journal of Biochemistry, 2000
- Molecular mechanisms of development of the gastrointestinal tractDevelopmental Dynamics, 2000
- Mutations in the SMAD4/DPC4 Gene in Juvenile PolyposisScience, 1998
- Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndromeNature Genetics, 1997
- Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients.Proceedings of the National Academy of Sciences, 1992