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

Johan H van Es; Marielle E van Gijn; Orbicia Riccio; Maaike van den Born; Marc Vooijs; Harry Begthel; Miranda Cozijnsen; Sylvie Robine; Doug J Winton; Freddy Radtke; Hans Clevers

doi:10.1038/nature03659

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

Nature. 2005 Jun 16;435(7044):959-63. doi: 10.1038/nature03659.

Authors

Johan H van Es¹, Marielle E van Gijn, Orbicia Riccio, Maaike van den Born, Marc Vooijs, Harry Begthel, Miranda Cozijnsen, Sylvie Robine, Doug J Winton, Freddy Radtke, Hans Clevers

Affiliation

¹ Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.

PMID: 15959515
DOI: 10.1038/nature03659

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 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. We obtained a similar phenotype by blocking the Notch cascade with a gamma-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 gamma-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoma / enzymology
Adenoma / genetics
Adenoma / metabolism
Adenoma / pathology*
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
Cell Differentiation / drug effects
Cell Proliferation / drug effects*
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Dibenzazepines / pharmacology
Endopeptidases / metabolism*
Female
Genes, APC
Goblet Cells / cytology*
Goblet Cells / drug effects
Goblet Cells / metabolism
Goblet Cells / pathology
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Intestine, Small / cytology*
Intestine, Small / drug effects
Intestine, Small / enzymology
Intestine, Small / metabolism
Male
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Nuclear Proteins / deficiency
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phenotype
Protease Inhibitors / pharmacology*
Receptors, Notch
Signal Transduction / drug effects

Substances

DNA-Binding Proteins
Dibenzazepines
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Membrane Proteins
Nuclear Proteins
Protease Inhibitors
Rbpj protein, mouse
Receptors, Notch
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
Bace1 protein, mouse