Differential regulation of communication by retinoic acid in homologous and heterologous junctions between normal and transformed cells

The permeability of junctions between cells of the same type (homologous junctions) is greatly increased by retinoic acid (10^-9-10^-8 M), a probable morphogen, and this responsiveness is shared by a variety of normal and transformed cell types (Mehta, P. P., J. S. Bertram, and W. R. Loewenstein. 1989. J. Cell Biol. 108:1053-1065). Here we report that the heterologous junctions between the normal and transformed cells respond in the opposite direction; their permeability is reduced by retinoic acid (≥10^-9 M) and (its benzoic acid derivative tetrahydrotetramethylnaph-thalenylpropenylbenzoic acid (≥10^-11 M). The opposite responses of the two classes of junction are shown to be concurrent; in cocultures of normal 10T1/2 cells and their methylcholanthrene-transformed counterparts, the permeability of the heterologous junctions, which is lower than that of the homologous junctions to start with, falls (within 20 h of retinoid application), at the same time that the permeability of the homologous junctions rises in both cell types. Such a counter-regulation requires a minimum of three degrees of cellular differentiation. A model is proposed in which the differentiations reside in a trio of junctional channel protein. The principle of the model may have wide applications in the regulation of intercellular communication at tissue boundaries, including embryonic ones.