Requirement of notch activation during regeneration of the intestinal epithelia

Ryuichi Okamoto, Kiichiro Tsuchiya, Yasuhiro Nemoto, Junko Akiyama, Tetsuya Nakamura, Takanori Kanai, Mamoru Watanabe

Research output: Contribution to journalArticlepeer-review

139 Citations (Scopus)


Notch signaling regulates cell differentiation and proliferation, contributing to the maintenance of diverse tissues including the intestinal epithelia. However, its role in tissue regeneration is less understood. Here, we show that Notch signaling is activated in a greater number of intestinal epithelial cells in the inflamed mucosa of colitis. Inhibition of Notch activation in vivo using a γ-secretase inhibitor resulted in a severe exacerbation of the colitis attributable to the loss of the regenerative response within the epithelial layer. Activation of Notch supported epithelial regeneration by suppressing goblet cell differentiation, but it also promoted cell proliferation, as shown in in vivo and in vitro studies. By utilizing tetracycline-dependent gene expression and microarray analysis, we identified a novel group of genes that are regulated downstream of Notch1 within intestinal epithelial cells, including PLA2G2A, an antimicrobial peptide secreted by Paneth cells. Finally, we show that these functions of activated Notch1 are present in the mucosa of ulcerative colitis, mediating cell proliferation, goblet cell depletion, and ectopic expression of PLA2G2A, thereby contributing to the regeneration of the damaged epithelia. This study showed the critical involvement of Notch signaling during intestinal tissue regeneration, regulating differentiation, proliferation, and antimicrobial response of the epithelial cells. Thus Notch signaling is a key intracellular molecular pathway for the proper reconstruction of the intestinal epithelia.

Original languageEnglish
Pages (from-to)G23-G35
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number1
Publication statusPublished - 2009 Jan
Externally publishedYes


  • Goblet cells
  • Intestinal epithelial cells
  • PLA2G2A
  • Ulcerative colitis

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


Dive into the research topics of 'Requirement of notch activation during regeneration of the intestinal epithelia'. Together they form a unique fingerprint.

Cite this