TY - JOUR
T1 - Intestinal Deletion of Pofut1 in the Mouse Inactivates Notch Signaling and Causes Enterocolitis
AU - Guilmeau, Sandra
AU - Flandez, Marta
AU - Bancroft, Laura
AU - Sellers, Rani S.
AU - Tear, Benjamin
AU - Stanley, Pamela
AU - Augenlicht, Leonard H.
N1 - Funding Information:
Supported by NCI grants RO1 CA114265 and U54 CA100926 to LH Augenlicht and RO1 CA95022 to Pamela Stanley, by the Philippe Foundation, and by the Albert Einstein Cancer Center grant PO1 13330.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=51249120100&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=51249120100&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2008.05.050
DO - 10.1053/j.gastro.2008.05.050
M3 - Article
C2 - 18621050
AN - SCOPUS:51249120100
SN - 0016-5085
VL - 135
SP - 849-860.e6
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -