Notch signaling regulates proliferation and differentiation of the intestinal crypt base columnar (CBC) stem cell

Abstract

This study examined the importance of the Notch signaling pathway for homeostasis of the CBC stem cell in the intestine. The Lgr5‐GFP reporter mouse strain was used to identify and track CBC stem cells after Notch inhibition with DBZ. Global Notch disruption in adult mice induced rapid CBC cell loss, with reduced proliferation and apoptotic cell death. Furthermore, expression of the CBC stem cell‐specific marker Olfactomedin 4 (Olfm4) was observed to be directly dependent on Notch signaling, with transcription activated through RBP‐Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitor cells into secretory cell types, including goblet, enteroendocrine and tuft cells, as well as an unusual secretory cell type that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1‐deficient mouse intestine demonstrated that the generalized secretory cell hyperplasia induced by Notch inhibition was dependent on this transcription factor, whereas Notch regulation of Olfm4 gene expression was Atoh1‐independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice in order to control epithelial cell proliferation and differentiation.