Notch/gamma-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. 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.
- URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15959515
Keywords: Adenoma/enzymology/genetics/metabolism/*pathology ; Animals ; Cell Differentiation/drug effects ; Cell Proliferation/*drug effects ; DNA-Binding Proteins/deficiency/genetics/metabolism ; Dibenzazepines/pharmacology ; Endopeptidases/*metabolism ; Female ; Genes ; APC ; Goblet Cells/*cytology/drug effects/metabolism/pathology ; Immunoglobulin J Recombination Signal Sequence-Binding Protein ; Intestine ; Small/*cytology/drug effects/enzymology/metabolism ; Male ; Membrane Proteins/*antagonists & inhibitors/metabolism ; Mice ; Mice ; Inbred C57BL ; Nuclear Proteins/deficiency/genetics/metabolism ; Phenotype ; Protease Inhibitors/*pharmacology ; Receptors ; Notch ; Research Support ; Non-U.S. Gov't ; Signal Transduction/drug effects
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
Record created on 2006-12-05, modified on 2016-08-08