Lgl resets Par complex membrane loading at mitotic exit to polarize neural stem cells

The Par complex regulates cell polarity in diverse animal cells, but how its localization is restricted to a specific membrane domain remains unclear. We investigate how the tumor suppressor Lethal giant larvae (Lgl) regulates Par complex polarity in Drosophila neural stem cells (NSCs). Unlike in epithelial cells, where Lgl and the Par complex show mutual exclusion, in NSCs the Par complex is apically polarized while Lgl is cytoplasmic during mitosis. We demonstrate that Lgl’s primary function is to remove the Par complex from the membrane at mitotic exit, resetting polarity for the next cell cycle. In Lgl-depleted NSCs, the Par complex persists on both apical and basal membranes throughout the cell cycle. Surprisingly, apical Par complex targeting and polarization occur independently of Lgl, but residual basal Par complex is sufficient to disrupt asymmetric division. These findings reveal a novel mechanism of negative polarity regulation by Lgl and highlight the importance of the pre-polarized state in Par-mediated polarity.