Drosophila tumor suppressors maintain epithelial integrity by controlling mitotic spindle orientation. Yu-ichiro Nakajima, Emily Meyer, Matthew Gibson. Stowers Institute for Medical Research, Kansas City, MO.

   During epithelial cell proliferation, planar alignment of the mitotic spindle coordinates the local process of symmetric cell cleavage with the global maintenance of polarized tissue architecture. While the disruption of planar spindle alignment is hypothesized to cause epithelial dysplasia and cancer development, the in vivo mechanisms regulating mitotic spindle orientation remain elusive. Here, we show that in Drosophila wing imaginal discs, the Actomyosin cortex and junction-localized neoplastic tumor suppressors Scribble (Scrib) and Discs Large (Dlg) play essential roles in planar spindle alignment and thus the control of epithelial integrity. During wing disc development, F-Actin is accumulated at the cortex of mitotic cells and mitotic spindles align at the level of the septate junctions. Inhibitions of cortical Actomyosin by drug perturbation or dsRNA knockdown of actin regulators (rho-kinase/moesin) lead to severe misorientation of the mitotic spindle. Disruptions of the septate-junction localized scaffold proteins Scrib/Dlg do not cause loss of epithelial polarity as an initial phenotype, but rather do induce misalignment of the mitotic spindle. We further show that defective alignment of the mitotic spindle correlates with basal cell extrusion and increased cell death. Blocking cell death in misaligned cells is alone sufficient to cause epithelial-to-mesenchymal transition and drive the formation of basally extruded tumor-like masses. These findings demonstrate a key role for junction-mediated spindle alignment in the maintenance of epithelial integrity, and also reveal a novel cell death-mediated tumor suppressor function inherent in the polarized architecture of epithelia.