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 architecture1,2. Although the disruption of planar spindle alignment is proposed to cause epithelial to mesenchymal transition and cancer3,4,5,6, 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.
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Acknowledgements
We thank D. Bilder, M. Miura, Y. Yamashita, the Bloomington Stock Center, Vienna Drosophila RNAi Center, TRiP, and FlyTrap project for fly stocks and C. Doe, F. Matsuzaki and the Developmental Studies Hybridoma Bank for antibodies. We thank R. Fehon for suggestions. We thank T. Akiyama, A. Fritz, A. Ikmi and M. Szuperak for comments on the manuscript and L. Liang for technical advice. We also thank M. Gogol for graphical assistance, F. Guo for TEM support and L. Gutchewsky for administrative support. This work was supported by the Stowers Institute for Medical Research and the Burroughs Wellcome Fund for Biomedical Research.
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Y.-I.N. and M.C.G. conceived the project, designed the experiments and wrote the manuscript. Y.-I.N. and E.J.M. performed the experiments and analysed the data. A.K. and S.A.M. constructed the SPIM system and performed live imaging.
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This file contains Supplementary Figures 1-12, Supplementary Table 1, Supplementary Text and a Supplementary Reference. (PDF 19314 kb)
Planar cell division and its consequence in a control wing disc
Time-lapse video monitoring a planar cell division and its consequence in a control wing disc. Cnn-GFP (green) was expressed in the nub-Gal4 domain and His-RFP labeled all nuclei. Scale bar, 5 μm. (related to Supplementary Fig. 10d). (AVI 3005 kb)
Misoriented cell division and its consequence in a rok-RNAi wing disc.
Time-lapse video monitoring a misoriented cell division and its consequence in a rok-RNAi wing disc. Cnn-GFP (green) and rok-RNAi were expressed in the nub-Gal4 domain and His-RFP labeled all nuclei (magenta). Scale bar, 5 μm. (related to Supplementary Fig. 10e) (AVI 3929 kb)
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Nakajima, Yi., Meyer, E., Kroesen, A. et al. Epithelial junctions maintain tissue architecture by directing planar spindle orientation. Nature 500, 359–362 (2013). https://doi.org/10.1038/nature12335
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DOI: https://doi.org/10.1038/nature12335
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