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.
van Es
Johan H
JH
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
van Gijn
Marielle E
ME
Riccio
Orbicia
O
van den Born
Maaike
M
Vooijs
Marc
M
Begthel
Harry
H
Cozijnsen
Miranda
M
Robine
Sylvie
S
Winton
Doug J
DJ
Radtke
Freddy
F
Clevers
Hans
H
D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D017491:Genes, APC; D020397:Goblet Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007421:Intestine, Small / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology*; D051880:Receptors, Notch; D015398:Signal Transduction / Q000187:drug effects
D004268:DNA-Binding Proteins; D003984:Dibenzazepines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011480:Protease Inhibitors; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse