Cdx1 or Cdx2 expression activates E-cadherin-mediated cell-cell adhesion and compaction in human COLO 205 cells

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Abstract
A mature columnar intestinal epithelium develops late in embryogenesis and is maintained throughout the life of the organism. Although the mechanisms driving intestine-specific gene expression have been well studied, those promoting the acquisition of cell-cell junctions, columnar morphogenesis, and polarization have been less studied. The Cdx homeodomain transcription factors (Cdx1 and Cdx2) regulate intestine-specific gene expression and intestinal epithelial differentiation. We report here that Cdx expression induces E-cadherin activity and cell-cell adhesion in human COLO 205 cancer cells. Within days of Cdx1 or Cdx2 expression, a new homotypic cell-cell adhesion phenotype is induced. This is a specific response to Cdx, inasmuch as a Cdx1 mutant failed to elicit the effect. Additionally, Cdx-expressing COLO 205 cells demonstrate a reduced proliferative capacity and an increase in the mRNA expression of differentiation-associated genes. Electron micrographs of these cells demonstrate induction of tight, adherens, and desmosomal junctions, as well as a columnar shape and apical microvilli. Investigations of the adhesion phenotype determined that it was Ca2+dependent and could be blocked by an E-cadherin-blocking antibody. However, E-cadherin protein levels and intracellular distribution were unchanged. Cdx expression restored the ability of the cell membranes to adhere and undergo compaction. We conclude that Cdx1 or Cdx2 expression is sufficient to induce an E-cadherin-dependent adhesion of COLO 205 cells. This adhesion is associated with polarization and cell-cell membrane compaction, as well as induction of a differentiated gene-expression pattern. Ascertaining the mechanism for this novel Cdx effect may yield insight into the development of mature colonic epithelium.