Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.

O. Riccio; M.E. van Gijn; A.C. Bezdek; L. Pellegrinet; J.H. van Es; U. Zimber-Strobl; L.J. Strobl; T. Honjo; H. Clevers; F. Radtke

doi:10.1038/embor.2008.7

Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.

O. Riccio, M.E. van Gijn, A.C. Bezdek, L. Pellegrinet, J.H. van Es, U. Zimber-Strobl, L.J. Strobl, T. Honjo, H. Clevers, F. Radtke

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

336 Citations (Scopus)

Abstract

The crucial role of individual Notch receptors and the mechanism by which they maintain intestinal crypt progenitor cells were assessed by using a series of inducible gut-specific Notch mutant mice. We found that Notch1 and Notch2 receptors function redundantly in the gut, as only simultaneous loss of both receptors results in complete conversion of proliferating crypt progenitors into post-mitotic goblet cells. This conversion correlates with the loss of Hes1 expression and derepression of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2. We also found that the promoter of both CDK inhibitor genes is occupied by the Notch effector Hes1 in wild-type crypt progenitor cells. Thus, our results indicate that Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by transcriptionally repressing two CDK inhibitors.

Original language	English
Pages (from-to)	377-383
Journal	EMBO Reports
Volume	9
Issue number	4
DOIs	https://doi.org/10.1038/embor.2008.7
Publication status	Published - 2008

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Riccio, O., van Gijn, M. E., Bezdek, A. C., Pellegrinet, L., van Es, J. H., Zimber-Strobl, U., Strobl, L. J., Honjo, T., Clevers, H., & Radtke, F. (2008). Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Reports, 9(4), 377-383. https://doi.org/10.1038/embor.2008.7

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title = "Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.",

abstract = "The crucial role of individual Notch receptors and the mechanism by which they maintain intestinal crypt progenitor cells were assessed by using a series of inducible gut-specific Notch mutant mice. We found that Notch1 and Notch2 receptors function redundantly in the gut, as only simultaneous loss of both receptors results in complete conversion of proliferating crypt progenitors into post-mitotic goblet cells. This conversion correlates with the loss of Hes1 expression and derepression of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2. We also found that the promoter of both CDK inhibitor genes is occupied by the Notch effector Hes1 in wild-type crypt progenitor cells. Thus, our results indicate that Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by transcriptionally repressing two CDK inhibitors.",

author = "O. Riccio and {van Gijn}, M.E. and A.C. Bezdek and L. Pellegrinet and {van Es}, J.H. and U. Zimber-Strobl and L.J. Strobl and T. Honjo and H. Clevers and F. Radtke",

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Riccio, O, van Gijn, ME, Bezdek, AC, Pellegrinet, L, van Es, JH, Zimber-Strobl, U, Strobl, LJ, Honjo, T, Clevers, H & Radtke, F 2008, 'Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.', EMBO Reports, vol. 9, no. 4, pp. 377-383. https://doi.org/10.1038/embor.2008.7

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T1 - Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.

AU - Riccio, O.

AU - van Gijn, M.E.

AU - Bezdek, A.C.

AU - Pellegrinet, L.

AU - van Es, J.H.

AU - Zimber-Strobl, U.

AU - Strobl, L.J.

AU - Honjo, T.

AU - Clevers, H.

AU - Radtke, F.

N1 - Reporting year: 2008

PY - 2008

Y1 - 2008

N2 - The crucial role of individual Notch receptors and the mechanism by which they maintain intestinal crypt progenitor cells were assessed by using a series of inducible gut-specific Notch mutant mice. We found that Notch1 and Notch2 receptors function redundantly in the gut, as only simultaneous loss of both receptors results in complete conversion of proliferating crypt progenitors into post-mitotic goblet cells. This conversion correlates with the loss of Hes1 expression and derepression of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2. We also found that the promoter of both CDK inhibitor genes is occupied by the Notch effector Hes1 in wild-type crypt progenitor cells. Thus, our results indicate that Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by transcriptionally repressing two CDK inhibitors.

AB - The crucial role of individual Notch receptors and the mechanism by which they maintain intestinal crypt progenitor cells were assessed by using a series of inducible gut-specific Notch mutant mice. We found that Notch1 and Notch2 receptors function redundantly in the gut, as only simultaneous loss of both receptors results in complete conversion of proliferating crypt progenitors into post-mitotic goblet cells. This conversion correlates with the loss of Hes1 expression and derepression of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2. We also found that the promoter of both CDK inhibitor genes is occupied by the Notch effector Hes1 in wild-type crypt progenitor cells. Thus, our results indicate that Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by transcriptionally repressing two CDK inhibitors.

U2 - 10.1038/embor.2008.7

DO - 10.1038/embor.2008.7

M3 - Article

SN - 1469-221X

VL - 9

SP - 377

EP - 383

JO - EMBO Reports

JF - EMBO Reports

IS - 4

ER -

Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.

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