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Aberrant Stem Cell Differentiation in Mutant EpCAM Mice


Congenital Tufting Enteropathy (CTE) is a rare intestinal disease which presents in newborns, causing intestinal failure and failure to thrive. Mutations in EpCAM, Epithelial Cell Adhesion Molecule, have been shown to be causative in CTE. In addition to its role in mediating cell adhesion, EpCAM has also been linked to cell proliferation and differentiation. In this project, we investigated the role of EPCAM mutation on intestinal epithelial cell differentiation in the small intestine. To do so, adult inducible EpCAM4/4 mice were used to investigate these changes. We found there to be severe decreases in secretory lineages (Paneth, goblet, enteroendocrine) in mutant mice along with characteristic tufting of the villi. We also noted changes in differentiation factor levels via qPCR and immunoblotting. Atoh1 was decreased at both the RNA and protein levels, along with a decrease in Klf4, which is implicated in terminal goblet cell differentiation, at the RNA level. We also discovered increased NOTCH1 signaling via immunoblot, which activates the enterocyte differentiation pathway. Therefore, we conclude that in the presence of mutated EpCAM, there is improper differentiation signaling upon intestinal stem cells leading to a reduction in secretory cell lineages.

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