Abstract
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 axis1. 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Batlle, E., Sancho, E. & Clevers, H. Signaling pathways in intestinal development and cancer. Annu. Rev. Cell Dev. Biol. 20, 695–723 (2004)
Artavanis-Tsakonas, S. R., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999)
Baron, M. An overview of the Notch signalling pathway. Semin. Cell Dev. Biol. 14, 113–119 (2003)
Heitzler, P., Bourouis, M., Ruel, L., Carteret, C. & Simpson, P. 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. Development 122, 161–171 (1996)
Oellers, N., Dehiom, M. & Knustm, E. bHLH proteins encoded by the Enhancer of split complex of Drosophila negatively interfere with transcriptional activation mediated by proneural genes. Mol. Gen. Genet. 244, 465–473 (1994)
Crosnier, C. et al. Delta-Notch signaling controls commitment to a secretory fate in zebrafish intestine. Development 132, 1093–1104 (2005)
Schroder, N. & Gossler, A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr. Patterns 2, 247–250 (2002)
Sander, G. R. & Powell, B. C. Expression of Notch receptors and ligands in the adult gut. J. Histochem. Cytochem. 52, 509–516 (2004)
Ohtsuka, T. et al. Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation. EMBO J. 18, 2196–2207 (1999)
Jensen, J. et al. Control of endodermal endocrine development by Hes-1. Nature Genet. 24, 36–44 (2000)
Zheng, J. L., Shou, J., Guillemot, F., Kageyama, R. & Gao, W. Q. Hes1 is a negative regulator of inner ear hair cell differentiation. Development 127, 4551–4560 (2000)
Yang, Q., Bermingham, N. A., Finegold, M. J. & Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158 (2001)
De Strooper, B. et al. Presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999)
Kopan, R. & Goate, A. A common enzyme connects Notch signaling and Alzheimer's disease. Genes Dev. 14, 2799–2806 (2000)
Wong, G. T. et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 279, 12876–12882 (2004)
Milano, J. et al. Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol. Sci. 1, 341–358 (2004)
Searfoss, G. H. et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J. Biol. Chem. 278, 46107–46116 (2003)
Han, H. et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14, 637–645 (2002)
Ireland, H. et al. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology 126, 1236–1246 (2004)
el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004)
Fre, S. et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature doi:10.1038/nature03589 (this issue)
Bienz, M. & Clevers, H. Colorectal cancer to Wnt signaling. Cell 103, 311–320 (2000)
van de Wetering, M. et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002)
Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992)
Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998)
Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003)
Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004)
Citron, M. Strategies for disease modification in Alzheimer's disease. Nature Rev. Neurosci. 5, 677–685 (2004)
Moorman, A. F., Houweling, A. C., de Boer, P. A. & Christoffels, V. M. Sensitive nonradioactive detection of mRNA in tissue sections: novel application of the whole-mount in situ hybridization protocol. J. Histochem. Cytochem. 49, 1–8 (2001)
Acknowledgements
We thank T. Honjo for providing the floxed Rbp-J mice, D. Louvard for providing the vil-Cre-ERT2 mice, A. Gossler and J. Johnson for providing reagents, and R. Kopan for discussions. H.C. is supported by grants from the Koningin Wilhelmina Fonds, ZON-MW/Spinoza and the Louis Jeantet Foundation. F.R. and O.R. are in part supported by grants from Oncosuisse and the Swiss National Science Foundation. S.R. is supported by the Association pour la Recherche sur le Cancer and ACI Ministère de la Recherche: Biologie du développement et physiologie intégrative.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
J.H.v.E., M.E.v.G. and H.C. are named as inventors on a patent application proposing Notch/γ-secretase inhibition as a therapeutic strategy for intestinal neoplastic disease.
Supplementary information
Supplementary Table and Figures Legends
Legends to accompany the below Supplementary Table and Supplementary Figures. (DOC 24 kb)
Supplementary Table S1
Quantification of Math1 and BrdU positive cells in the crypt section of RBP-Jfloxed/floxed/P450-Cre mice at various times after Cre induction. (PPT 21 kb)
Supplementary Figure S1
Early changes upon disruption of Notch signalling in adult mouse intestine. (PDF 9408 kb)
Supplementary Figure S2
Disruption of Notch signalling pathway induces goblet cell conversion of crypt proliferative cells. (PDF 15026 kb)
Supplementary Figure S3
Conversion of proliferative crypt cells into post-mitotic goblet cells occurs in a cell-autonomous fashion. (PDF 3012 kb)
Supplementary Figure S4
Hes6 gene expression, limited to proliferative cells directly above the Paneth cell compartment in all crypts of the small intestine, becomes undetectable in the RBP-Jfloxed/floxed/P450-Cre mice after induction with β-naphtoflavone (B versus A). (PDF 2255 kb)
Rights and permissions
About this article
Cite this article
van Es, J., van Gijn, M., Riccio, O. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005). https://doi.org/10.1038/nature03659
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature03659
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.