Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells

The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt–villus axis. Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (ref. 2). We obtained a similar phenotype by blocking the Notch cascade with a γ-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that γ-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.

[1]  Hans Clevers,et al.  The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. , 2002, Cell.

[2]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[3]  M. Citron,et al.  Strategies for disease modification in Alzheimer's disease , 2004, Nature Reviews Neuroscience.

[4]  T. Honjo,et al.  Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. , 2002, International immunology.

[5]  Francois Pognan,et al.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[6]  H. Zoghbi,et al.  Requirement of Math1 for Secretory Cell Lineage Commitment in the Mouse Intestine , 2001, Science.

[7]  B. Powell,et al.  Expression of Notch Receptors and Ligands in the Adult Gut , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[8]  S. Artavanis-Tsakonas,et al.  Notch Signaling : Cell Fate Control and Signal Integration in Development , 1999 .

[9]  M. Baron,et al.  An overview of the Notch signalling pathway. , 2003, Seminars in cell & developmental biology.

[10]  Neil Vargesson,et al.  Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine , 2005, Development.

[11]  H. Clevers,et al.  Linking Colorectal Cancer to Wnt Signaling , 2000, Cell.

[12]  M. Dehio,et al.  bHLH proteins encoded by theEnhancer of split complex ofDrosophila negatively interfere with transcriptional activation mediated by proneural genes , 1994, Molecular and General Genetics MGG.

[13]  Antoon F. M. Moorman,et al.  Sensitive Nonradioactive Detection of mRNA in Tissue Sections: Novel Application of the Whole-mount In Situ Hybridization Protocol , 2001, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[14]  Daniel Metzger,et al.  Tissue‐specific and inducible Cre‐mediated recombination in the gut epithelium , 2004, Genesis.

[15]  K. Kinzler,et al.  Erratum: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene , 1992, Science.

[16]  Hans Clevers,et al.  Signaling pathways in intestinal development and cancer. , 2004, Annual review of cell and developmental biology.

[17]  S. Artavanis-Tsakonas,et al.  Notch signals control the fate of immature progenitor cells in the intestine. , 2005, Nature Reviews Molecular Cell Biology.

[18]  Hans Clevers,et al.  Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. , 2003, Genes & development.

[19]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[20]  Hans Clevers,et al.  Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4 , 1998, Nature Genetics.

[21]  R. Kageyama,et al.  Hes1 is a negative regulator of inner ear hair cell differentiation. , 2000, Development.

[22]  Ryoichiro Kageyama,et al.  Control of endodermal endocrine development by Hes-1 , 2000, Nature Genetics.

[23]  A. Goate,et al.  A common enzyme connects notch signaling and Alzheimer's disease. , 2000, Genes & development.

[24]  W. H. Jordan,et al.  Adipsin, a Biomarker of Gastrointestinal Toxicity Mediated by a Functional γ-Secretase Inhibitor* , 2003, Journal of Biological Chemistry.

[25]  Jay S. Fine,et al.  Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation* , 2004, Journal of Biological Chemistry.

[26]  P. Simpson,et al.  Genes of the Enhancer of split and achaete-scute complexes are required for a regulatory loop between Notch and Delta during lateral signalling in Drosophila. , 1996, Development.

[27]  A. Gossler,et al.  Expression of Notch pathway components in fetal and adult mouse small intestine. , 2002, Gene expression patterns : GEP.

[28]  O. Sansom,et al.  Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. , 2004, Gastroenterology.

[29]  T. Ohtsuka,et al.  Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation , 1999, The EMBO journal.