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 Rep. 2008 Apr;9(4):377-83. doi: 10.1038/embor.2008.7. Epub 2008 Feb 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / physiology*
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism*
  • DNA Primers / genetics
  • Gene Expression Regulation / genetics
  • Goblet Cells / cytology
  • Goblet Cells / metabolism*
  • Homeodomain Proteins / metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Receptor, Notch1 / metabolism*
  • Receptor, Notch2 / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Transcription Factor HES-1


  • Basic Helix-Loop-Helix Transcription Factors
  • Cyclin-Dependent Kinase Inhibitor p57
  • DNA Primers
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Receptor, Notch1
  • Receptor, Notch2
  • Transcription Factor HES-1
  • Cyclin-Dependent Kinase Inhibitor p27