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.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Guilmeau S,Flandez M,Bancroft L,Sellers RS,Tear B,Stanley P,Augenlicht LHdoi
10.1053/j.gastro.2008.05.050subject
Has Abstractpub_date
2008-09-01 00:00:00pages
849-60, 860.e1-6issue
3eissn
0016-5085issn
1528-0012pii
S0016-5085(08)00871-8journal_volume
135pub_type
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