Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27^Kip1 and p57^Kip2

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 p27 Kip1 and p57 Kip2 . 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.

Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling

“…However, when the Notch1 and Notch2 receptors were targeted by their cognate siRNAs simultaneously, there was, 48 h after transfection, a 32 and 51% reduction of Notch1 and Notch2 mRNA levels, respectively, which significantly enhanced Hath1, Tff3 and Muc2 expression by 72 h (Figure 5c). Thus, the two receptors appeared to act redundantly in the transformed HT29Cl16E cells, similar to their role in the normal intestinal epithelium (Riccio et al, 2008). Interestingly, although the goblet cell differentiation programme was effectively triggered by simultaneous downregulation of Notch1 and Notch2 by siRNA, there was no effect on cell proliferation (not shown), in contrast to the shRNA experiments that showed each to have modest effects on clonogenic growth.…”

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

“…23 Contrary to Drosophila, 38 Nle loss of function does not seem to interfere with the Notch pathway in the mouse hematopoietic 23 and intestinal (this study) lineages. Indeed, although increasing or decreasing Notch activity systematically results in strong variations of Hes1 expression levels in the intestinal crypt cells, [39][40][41][42][43] Hes1 mRNA levels were unchanged following Nle inactivation in the intestinal epithelium (Figure 3c and data not shown). Interestingly, premature differentiation toward the goblet cell lineage of intestinal stem/ progenitor cells is observed when Notch activity is inhibited.…”

“…Interestingly, premature differentiation toward the goblet cell lineage of intestinal stem/ progenitor cells is observed when Notch activity is inhibited. 39,[41][42][43] In view of our results, it would therefore be important to determine whether p53 participates in the hypersecretory phenotype of Notch-defective intestinal epithelium.…”

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

“…32,33 Because of the essential role for Notch signaling in stem cell maintenance and glial differentiation, we tested whether p57Kip2 could interact directly with the Notch signaling transcription factor CSL/RBP-Jk, but we failed to detect an interaction between these two factors in immunoprecipitation experiments (BJ, unpublished observations). We further did not find any interaction between p57Kip2 or Hes proteins.…”