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

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.

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Figure 1: Notch signalling pathway components are expressed in crypts of the small intestine.
Figure 2: Disruption of Notch signalling pathway induces goblet cell conversion of crypt proliferative cells.
Figure 3: Conversion of proliferative crypt cells into post-mitotic goblet cells by the γ-secretase inhibitor DBZ.
Figure 4: Conversion of proliferative cells in the Apc Min tumour into post-mitotic goblet cells by the γ-secretase inhibitor DBZ.

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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.

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Correspondence to Hans Clevers.

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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)

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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

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