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.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Riccio O,van Gijn ME,Bezdek AC,Pellegrinet L,van Es JH,Zimber-Strobl U,Strobl LJ,Honjo T,Clevers H,Radtke F

doi

10.1038/embor.2008.7

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

377-83

issue

4

eissn

1469-221X

issn

1469-3178

pii

embor20087

journal_volume

9

pub_type

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