In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death

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In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death

ML Hermiston and JI Gordon
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

A model system is described for defining the physiologic functions of mammalian cadherins in vivo. 129/Sv embryonic stem (ES) cells, stably transfected with a dominant negative N-cadherin mutant (NCAD delta) under the control of a promoter that only functions in postmitotic enterocytes during their rapid, orderly, and continuous migration up small intestinal villi, were introduced into normal C57B1/6 (B6) blastocysts. In adult B6<->129/Sv chimeric mice, each villus receives the cellular output of several surrounding monoclonal crypts. A polyclonal villus located at the boundary of 129/Sv- and B6-derived intestinal epithelium contains vertical coherent bands of NCAD delta- producing enterocytes plus adjacent bands of normal B6-derived enterocytes. A comparison of the biological properties of these cell populations established that NCAD delta disrupts cell-cell and cell- matrix contacts, increases the rate of migration of enterocytes along the crypt-villus axis, results in a loss of their differentiated polarized phenotype, and produces precocious entry into a death program. These data indicate that enterocytic cadherins are critical cell survival factors that actively maintain intestinal epithelial function in vivo.
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Coopersmith, C. M., Chandrasekaran, C., McNevin, M. S., Gordon, J. I. (1997). Bi-transgenic Mice Reveal that K-rasVal12 Augments a p53-independent Apoptosis When Small Intestinal Villus Enterocytes Reenter the Cell Cycle. JCB 138: 167-179 [Abstract] [Full Text]
Gniadecki, R., Gajkowska, B., Hansen, M. (1997). 1,25-Dihydroxyvitamin D3 Stimulates the Assembly of Adherens Junctions in Keratinocytes: Involvement of Protein Kinase C. Endocrinology 138: 2241-2248 [Abstract] [Full Text]
Kreft, B., Berndorff, D., Bottinger, A., Finnemann, S., Wedlich, D., Hortsch, M., Tauber, R., Gessner, R. (1997). LI-Cadherin-mediated Cell-Cell Adhesion Does Not Require Cytoplasmic Interactions. JCB 136: 1109-1121 [Abstract] [Full Text]
Chandrasekaran, C., Coopersmith, C. M., Gordon, J. I. (1996). Use of Normal and Transgenic Mice to Examine the Relationship between Terminal Differentiation of Intestinal Epithelial Cells and Accumulation of Their Cell Cycle Regulators. J. Biol. Chem. 271: 28414-28421 [Abstract] [Full Text]
Bry, L., Falk, P. G., Midtvedt, T., Gordon, J. I. (1996). A Model of Host-Microbial Interactions in an Open Mammalian Ecosystem. Science 273: 1380-1383 [Abstract]
Hermiston, M L, Wong, M H, Gordon, J I (1996). Forced expression of E-cadherin in the mouse intestinal epithelium slows cell migration and provides evidence for nonautonomous regulation of cell fate in a self-renewing system.. Genes Dev. 10: 985-996 [Abstract]
Uemura, T, Oda, H, Kraut, R, Hayashi, S, Kotaoka, Y, Takeichi, M (1996). Zygotic Drosophila E-cadherin expression is required for processes of dynamic epithelial cell rearrangement in the Drosophila embryo.. Genes Dev. 10: 659-671 [Abstract]
Li, Q., Karam, S. M., Gordon, J. I. (1996). Diphtheria Toxin-mediated Ablation of Parietal Cells in the Stomach of Transgenic Mice. J. Biol. Chem. 271: 3671-3676 [Abstract] [Full Text]