Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells

作者：VanDussen Kelli L; Carulli Alexis J; Keeley Theresa M; Patel Sanjeevkumar R; Puthoff Brent J; Magness Scott T; Tran Ivy T; Maillard Ivan; Siebel Christian; Kolterud Asa; Grosse Ann S; Gumucio Deborah L; Ernst Stephen A; Tsai Yu Hwai; Dempsey Peter J; Samuelson Linda C^*

来源：Development, 2012, 139(3): 488-497.

DOI：10.1242/dev.070763

• Olfactomedin 4
• Lgr5
• Atoh1
• Gamma-secretase inhibitor
• Tuft cell
• Mouse

Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-J kappa binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, 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 to control epithelial cell homeostasis.

• 出版日期2012-2-1