TY - JOUR
T1 - Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells
AU - Van Es, Johan H.
AU - Van Gijn, Marielle E.
AU - Riccio, Orbicia
AU - Van Den Born, Maaike
AU - Vooijs, Marc
AU - Begthel, Harry
AU - Cozijnsen, Miranda
AU - Robine, Sylvie
AU - Winton, Doug J.
AU - Radtke, Freddy
AU - Clevers, Hans
N1 - Funding Information:
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.
PY - 2005/6/16
Y1 - 2005/6/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=20544460148&partnerID=8YFLogxK
U2 - 10.1038/nature03659
DO - 10.1038/nature03659
M3 - Article
C2 - 15959515
AN - SCOPUS:20544460148
SN - 0028-0836
VL - 435
SP - 959
EP - 963
JO - Nature
JF - Nature
IS - 7044
ER -