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.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Chemin des Boveresses 155, Epalinges 1066, Switzerland.
authors.forename: Orbicia
authors.initials: O
authors.lastname: Riccio
authors.forename: Marielle E
authors.initials: ME
authors.lastname: van Gijn
authors.forename: April C
authors.initials: AC
authors.lastname: Bezdek
authors.forename: Luca
authors.initials: L
authors.lastname: Pellegrinet
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.forename: Lothar J
authors.initials: LJ
authors.lastname: Strobl
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D020397:Goblet Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D017931:DNA Primers; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse