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

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 β-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

[1]  N. Wright,et al.  Gastrointestinal stem cells , 2002, The Journal of pathology.

[2]  C. Eng,et al.  BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. , 2003, Human molecular genetics.

[3]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[4]  E. Fuchs,et al.  Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. , 2001, Genes & development.

[5]  V. Yong,et al.  PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. , 1999, European journal of biochemistry.

[6]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[7]  S. Dedhar,et al.  Tumor Suppressor Pten Inhibits Nuclear Accumulation of β-Catenin and T Cell/Lymphoid Enhancer Factor 1–Mediated Transcriptional Activation , 2001, The Journal of cell biology.

[8]  Francisca Vazquez,et al.  Phosphorylation of the PTEN Tail Regulates Protein Stability and Function , 2000, Molecular and Cellular Biology.

[9]  Haiyang Huang,et al.  Identification of the haematopoietic stem cell niche and control of the niche size , 2003, Nature.

[10]  Fumiko Itoh,et al.  Signaling of transforming growth factor‐β family members through Smad proteins , 2000 .

[11]  A. McMahon,et al.  Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. , 1998, Genes & development.

[12]  C. Eng,et al.  From developmental disorder to heritable cancer: it's all in the BMP/TGF-β family , 2003, Nature Reviews Genetics.

[13]  I. Weissman,et al.  A role for Wnt signalling in self-renewal of haematopoietic stem cells , 2003, Nature.

[14]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[15]  L. Aaltonen,et al.  Mutations in the SMAD4/DPC4 gene in juvenile polyposis. , 1998, Science.

[16]  R. Behringer,et al.  Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. , 1995, Genes & development.

[17]  T. Mak,et al.  Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production , 2003, Development.

[18]  A. Trumpp,et al.  Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the Pten Tumor Suppressor Gene in Vivo , 2001, Science.

[19]  C. Eng,et al.  From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. , 2003, Nature reviews. Genetics.

[20]  Hans Clevers,et al.  De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse Intestine , 2004, Science.

[21]  H. Clevers,et al.  Live and let die in the intestinal epithelium. , 2004, Current opinion in cell biology.

[22]  Caiying Guo,et al.  Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon cre‐mediated excision , 2000, Genesis.

[23]  J. Gordon,et al.  Use of transgenic mice to infer the biological properties of small intestinal stem cells and to examine the lineage relationships of their descendants. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[24]  K. Kinzler,et al.  Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Goumans,et al.  Signaling of transforming growth factor-beta family members through Smad proteins. , 2000, European journal of biochemistry.

[26]  D. Roberts,et al.  Molecular mechanisms of development of the gastrointestinal tract , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[27]  José Luis de la Pompa,et al.  Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN , 1998, Cell.

[28]  J. García-Verdugo,et al.  Noggin Antagonizes BMP Signaling to Create a Niche for Adult Neurogenesis , 2000, Neuron.

[29]  G. Mutter,et al.  Pten, a protean tumor suppressor. , 2001, The American journal of pathology.

[30]  E. Fuchs,et al.  Links between signal transduction, transcription and adhesion in epithelial bud development , 2003, Nature.

[31]  Christopher S Potten,et al.  Intestinal stem cells protect their genome by selective segregation of template DNA strands. , 2002, Journal of cell science.

[32]  Victor E. Velculescu,et al.  Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis , 2001, Nature Genetics.