Intestinal Deletion of Pofut1 in the Mouse Inactivates Notch Signaling and Causes Enterocolitis

Sandra Guilmeau, Marta Flandez, Laura Bancroft, Rani S. Sellers, Benjamin Tear, Pamela Stanley, Leonard H. Augenlicht

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Background & Aims: Notch downstream targets are fundamental to intestinal cell lineage commitment and are suggested as therapeutic targets for colon cancer cells. However, the role of endogenous Notch signaling through receptor-ligand interaction, and effects of its longer term down-regulation on intestinal homeostasis, are unclear. Methods: To address these issues, the gene encoding protein O-fucosyltransferase 1, an enzyme required for Notch ligand binding and thus activation of all Notch receptors, was deleted in the mouse intestinal and colonic epithelium, through Villin-Cre-mediated recombination. Results: Pofut1 deletion inactivated Notch signaling, giving rise to smaller but viable mice. These mice exhibited a large increase in all intestinal secretory cell lineages, which accumulated in the crypts, resulting in crypt hyperplasia. Although proliferating cells were largely reduced in the colon, the transit amplifying compartment was maintained in the upper crypts of the intestinal mucosa. By 9 months, these perturbations in cell maturation altered mucus-associated gut microbiota and caused chronic intestinal inflammation, with evidence of bacterial translocation to the mesenteric lymph nodes, macrophage, and T-lymphocyte infiltration, and Th1/Th17 immune response. Dysplastic foci were also observed in Pofut1-deficient small intestine with occasional progression to tumor formation. Conclusions: Mucus hypersecretion upon Pofut1 inactivation is accompanied by alteration of the mucus-associated flora, which likely contributes to the development of enterocolitis. Therefore, these data identify important potential complications in strategies to target Notch signaling in therapeutic approaches to colon cancer.

Original languageEnglish (US)
Pages (from-to)849-860.e6
JournalGastroenterology
Volume135
Issue number3
DOIs
StatePublished - Sep 2008

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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