Epithelial junctions maintain tissue architecture by directing planar spindle orientation

Abstract

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. Although the disruption of planar spindle alignment is proposed to cause epithelial to mesenchymal transition and cancer, the in vivo mechanisms regulating mitotic spindle orientation remain elusive. Here we demonstrate that the actomyosin cortex and the junction-localized neoplastic tumour suppressors Scribbled and Discs large 1 have essential roles in planar spindle alignment and thus the control of epithelial integrity in the Drosophila imaginal disc. We show that defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and that blocking the death of misaligned cells is sufficient to drive the formation of basally localized tumour-like masses. These findings indicate a key role for junction-mediated spindle alignment in the maintenance of epithelial integrity, and also reveal a previously unknown cell-death-mediated tumour-suppressor function inherent in the polarized architecture of epithelia.

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture

“…organisms and mammalian cell lines conclude that multiple regulators of the actin cytoskeleton, such as Rho kinases, Cdc42 and ERM-family proteins, are necessary for correct spindle orientation (Jaffe et al, 2008;Kunda et al, 2008;Nakajima et al, 2013;Yu et al, 2003). Studies in both Drosophila and mammalian cells also indicate that specific basolateral junctional proteins help to polarize cell division, raising the possibility that cell-cell junctions can cooperate with the cortical cytoskeleton to transmit external forces to orient cell division (den Elzen et al, 2009;Nakajima et al, 2013;Tuncay et al, 2015).…”

Mechanical control of mitotic progression in single animal cells

“…I n mitosis, eukaryotic cells down-regulate focal adhesions and increase their cortical tension and intracellular pressure, thereby generating force to round up against external impediments (1)(2)(3). Recent studies in the epithelium and epidermis of various organisms indicate that mitotic cell rounding is involved in tissue organization, development, and homeostasis (4)(5)(6)(7)(8). Abnormal mitotic cell shape can have adverse consequences for chromosome segregation and tissue growth (9), in some cases contributing to tumorigenesis (7).…”

“…Recent studies in the epithelium and epidermis of various organisms indicate that mitotic cell rounding is involved in tissue organization, development, and homeostasis (4)(5)(6)(7)(8). Abnormal mitotic cell shape can have adverse consequences for chromosome segregation and tissue growth (9), in some cases contributing to tumorigenesis (7). Despite the importance of cell rounding in mitotic progression and tissue organization, the mechanical robustness of mitotic cells remains poorly investigated even in vitro, probably due to a paucity of suitable experimental tools that can apply precise forces to poorly adherent cells.…”

The force and effect of cell proliferation

“…Although it has been recognized that defects in apico-basal polarity lead to spindle misalignment and disruption of epithelial architecture, the molecular mechanisms underlying this regulation are still unknown. Recent work in the Drosophila wing disc epithelium uncovered that the junctional proteins Scribbled and Discs large 1 (Dlg1) are required for proper spindle alignment parallel to the tissue plane (Nakajima et al, 2013). Similarly, in the Drosophila follicular epithelium, spindle orientation is dependent on the lateral localization of Dlg1, independently of its role in apico-basal polarity (Bergstralh et al, 2013).…”