BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling

Nat Genet. 2004 Oct;36(10):1117-21. doi: 10.1038/ng1430. Epub 2004 Sep 19.

Abstract

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. 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 beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / etiology
  • Adenomatous Polyposis Coli / genetics
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Proteins / physiology*
  • Cytoskeletal Proteins / physiology*
  • Disease Models, Animal
  • Epithelial Cells / pathology
  • Humans
  • Intestines / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • PTEN Phosphohydrolase
  • Protein Tyrosine Phosphatases / physiology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / physiology
  • Signal Transduction
  • Stem Cells / cytology
  • Trans-Activators / physiology*
  • Tumor Suppressor Proteins / physiology
  • Wnt Proteins
  • beta Catenin

Substances

  • Bone Morphogenetic Proteins
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • Trans-Activators
  • Tumor Suppressor Proteins
  • Wnt Proteins
  • beta Catenin
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • BMPR1A protein, human
  • Bmpr1a protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I
  • Protein Tyrosine Phosphatases
  • PTEN Phosphohydrolase
  • Pten protein, mouse