Abstract
Congenital tufting enteropathy (CTE) is a life-threatening hereditary disease that is characterized by enteric mucosa tufting degeneration and early onset, severe diarrhea. Loss-of-function mutations of the human EPCAM gene (TROP1, TACSTD1) have been indicated as the cause of CTE. However, loss of mTrop1/Epcam in mice appeared to lead to death in utero, due to placental malformation. This and indications of residual Trop-1/EpCAM expression in cases of CTE cast doubt on the role of mTrop1/Epcam in this disease. The aim of this study was to determine the role of TROP1/EPCAM in CTE and to generate an animal model of this disease for molecular investigation and therapy development. Using a rigorous gene-trapping approach, we obtained mTrop1/Epcam -null (knockout) mice. These were born alive, but failed to thrive, and died soon after birth because of hemorrhagic diarrhea. The intestine from the mTrop1/Epcam knockout mice showed intestinal tufts, villous atrophy and colon crypt hyperplasia, as in human CTE. No structural defects were detected in other organs. These results are consistent with TROP1/EPCAM loss being the cause of CTE, thus providing a viable animal model for this disease, and a benchmark for its pathogenetic course. In the affected enteric mucosa, E-cadherin and β-catenin were shown to be dysregulated, leading to disorganized transition from crypts to villi, with progressive loss of membrane localization and increasing intracellular accumulation, thus unraveling an essential role for Trop-1/EpCAM in the maintenance of intestinal architecture and functionality.Supporting information is available for this article.
Highlights
EpCAM, known as Trop-1, from the trophoblast cells in which it was originally defined [1], is a transmembrane glycoprotein [2,3,4] that shares unique structural features with its paralog Trop-2 [5,6]
We succeeded in obtaining embryonic stem (ES) cells with one inactivated mTrop1 allele
Two genetrapped ES clones were identified, i.e., RST412 and RST413, where mTrop1 was demonstrated to be inactivated by insertion of a promoterless bGEO cassette (Fig. 1A, C; Text S1), with 59 rapid amplification of cDNA ends (RACE) used for sequence validation
Summary
EpCAM, known as Trop-1, from the trophoblast cells in which it was originally defined [1], is a transmembrane glycoprotein [2,3,4] that shares unique structural features with its paralog Trop-2 [5,6]. Both Trop-1 and Trop-2 regulate cell-cell adhesion [7,8] and cell growth [4,9,10]. Trop-1 is a marker of adult epithelial and hematopoietic progenitors, and of proliferating epithelia [4,12]
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