Polarity dependent Hippo-Yap regulation controls cortical development

Epithelial polarity is established by partitioning the apical and basal domains within the cell. Antagonistic inhibitions between the apical and basal polarity complex proteins segregate them into their designated domains. Failure to achieve this causes developmental disorders and cancer. While the biochemical basis of this antagonism has been identified, the complexity of context-dependent cell-cell interactions obscures its cellular underpinnings. Here, through a series of genetic rescues in a murine model of brain malformation, the cellular mechanisms underlying this antagonism are uncovered. The expanded apical domain caused by the absence of the basal complex protein, Lethal Giant Larvae (Lgl)1 initiates subsequent cellular defects, including mislocalized adherens junctions and ectopic proliferation. Concurrent genetic removal of apical polarity complex, Crb1/2, abrogates cellular defects and heterotopia, evidence of their pivotal role. Gene expression, cell cycle, and rescue experiments revealed that antagonistic interactions converge onto Hippo-Yap signaling-dependent cell cycle kinetics. Our study highlights the fundamental antagonism of polarity proteins in preventing epithelial disruption and ectopic mitogenic activity.