PTEN-deficient intestinal stem cells initiate intestinal polyposis

Xi C. He, Tong Yin, Justin C. Grindley, Qiang Tian, Toshiro Sato, W. Andy Tao, Raminarao Dirisina, Kimberly S. Porter-Westpfahl, Mark Hembree, Teri Johnson, Leanne M. Wiedemann, Terrence A. Barrett, Leroy Hood, Hong Wu, Linheng Li

Research output: Contribution to journalArticlepeer-review

374 Scopus citations


Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector β-catenin. Akt phosphorylates β-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of β-catenin.

Original languageEnglish
Pages (from-to)189-198
Number of pages10
JournalNature Genetics
Issue number2
StatePublished - Feb 2007

Bibliographical note

Funding Information:
We are grateful to B. Neaves and R. Krumlauf for scientific support. We thank H. Okano for providing anti-Musashi1 (14-H1) and A. Ouellette for anti-cryptdin; S. Peck and G. Yang for comments on the manuscript; D. di Natale for assistance on manuscript editing; P. Kulesa and D. Stark for imaging assistance; C. Seidel, K. Zueckert-Gaudenz and M. Coleman for assistance in microarray analysis; H. Marshall for technology support and J. Chen for assistance in statistical analysis. L. Li is supported in part by research grant 5-FY05-31 from the March of Dimes Birth Defects Foundation, by grant R01 DK070001 from the National Institute of Diabetes and Digestive and Kidney Diseases and by the Stowers Institute for Medical Research.

ASJC Scopus subject areas

  • Genetics


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