Nature Genetics
36, 1117 - 1121 (2004)
Published online: 19 September 2004; | doi:10.1038/ng1430
BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt− -catenin signalingXi C He1, 6, Jiwang Zhang1, 6, Wei-Gang Tong1, Ossama Tawfik2, Jason Ross1, David H Scoville1, 2, Qiang Tian3, Xin Zeng4, Xi He4, Leanne M Wiedemann1, 2, Yuji Mishina5
& Linheng Li1, 21
Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, Missouri 64110, USA. 2
Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, Kansas 66160, USA. 3
Institute of Systemsbiology, Seattle, Washington 98103, USA. 4
Children's Hospital and Harvard University Medical School, Boston, Massachusetts 02115, USA. 5
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. 6
These two authors contributed equally to this work.
Correspondence should be addressed to Linheng Li lil@stowers-institute.orgIn 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  -catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.
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