Figure 9.

Model. Par1b inhibits an ECM–RhoA–RhoK pathway to promote hepatocytic lumen polarity and to regulate mitotic spindle orientation. Par1b-mediated inhibition of ECM-RhoA signaling in nonpolarized cells causes single or no cortical LGN–NuMA crescents in metaphase, leaving shape-sensing mechanisms to dictate spindle orientation (Grill and Hyman, 2005). RhoA inhibition also promotes polarization of these cells with hepatocytic polarity where the highest RhoA activity in metaphase presents adjacent to the lateral lumen and results in a robust cue for the recruitment of the LGN–NuMA complex to the subluminal domain and to a stereotypic spindle orientation shaped by the combination of the NuMA cue and the geometric constraints of the cell. The asymmetric deposition of a strong basal lamina as observed at lower Par1b signaling levels is associated with higher RhoA activity, which favors polarization with apical luminal domains (columnar polarity). In columnar epithelia, high cortical RhoA activity in metaphase is present along the sub-apical adhesion belt parallel to the basal surface, allowing Gαi (not depicted) and LGN–NuMA recruitment. A Ran-GTP gradient emanating from the chromosomes prevents LGN–NuMA from attaching to cortical regions closest to the metaphase plate (Kiyomitsu and Cheeseman, 2012), resulting in two LGN–NuMA crescents at two opposite membrane domains that align the spindle with the substratum. See Discussion for further explanations.