CPEB mediated ZO-1 mRNA Localization is Required for Epithelial Tight Junction Assembly and Cell Polarity

CPEB is a translational regulatory sequence-specific RNA binding protein that controls germ cell development. Here we show that CPEB heterozygous female mice are fertile but contain disorganized mammary epithelial cells in which ZO-1 and claudin-3, apical tight junction proteins, are mis-localized. CPEB depletion from mammary epithelial cells disrupts ZO-1 apical localization and tight junction distribution; conversely, ectopic expression of CPEB enhances ZO-1 localization. CPEB and ZO-1 mRNA are co-localized apically and ZO-1 3’UTR binding sites for CPEB are necessary for RNA localization. In a 3-dimensional culture system that models lumen-containing mammary ducts, depletion of CPEB or ZO-1 impairs central cavity formation, indicating a loss of cell polarity. Cavity formation in ZO-1 depleted cells is rescued when they are transduced with ZO-1 mRNA containing, but not lacking, CPEB binding sites. Our data demonstrates that CPEB-mediated ZO-1 mRNA localization is essential for tight junction assembly and mammary epithelial cell polarity.