Morphogenetic mechanisms of epithelial tubulogenesis: MDCK cell polarity is transiently rearranged without loss of cell-cell contact during scatter factor/hepatocyte growth factor-induced tubulogenesis.

Many organ systems are composed of networks of epithelial tubes. Recently, molecules that induce development of epithelial tubules and regulate sites of branching have been identified. However, little is known about the mechanisms regulating cell rearrangements that are necessary for tubule formation. In this study we have used a scatter factor/hepatocyte growth factor-induced model system of MDCK epithelial cell tubulogenesis to analyze the mechanisms of cell rearrangement during tubule development. We examined the dynamics of cell polarity and cell-cell junctions during tubule formation and present evidence for a multistep model of tubulogenesis in which cells rearrange without loss of cell-cell contacts and tubule lumens form de novo. A three-dimensional analysis of markers for apical and basolateral membrane subdomains shows that epithelial cell polarity is transiently lost and subsequently regained during tubulogenesis. Furthermore, components of cell-cell junctional complexes undergo profound rearrangements: E-cadherin is randomly distributed around the cell surface, desmoplakins I/II accumulate intracellularly, and the tight junction protein ZO-1 remains localized at sites of cell-cell contact. This suggests that differential regulation of cell-cell junctions is important for the formation of tubules. Therefore, during tubulogenesis, cell-cell adhesive contacts are differentially regulated while the polarity and specialization of plasma membrane subdomains reorganize, enabling cells to remain in contact as they rearrange into new structures.