Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2.
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.
Riccio
Orbicia
O
Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Chemin des Boveresses 155, Epalinges 1066, Switzerland.
van Gijn
Marielle E
ME
Bezdek
April C
AC
Pellegrinet
Luca
L
van Es
Johan H
JH
Zimber-Strobl
Ursula
U
Strobl
Lothar J
LJ
Honjo
Tasuku
T
Clevers
Hans
H
Radtke
Freddy
F
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
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