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Spindle reorientation in response to mechanical stress is an emergent property of the spindle positioning mechanisms

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Manasi Kelkar, Pierre Bohec, Matthew B. Smith, Varun Sreenivasan, Ana Lisica, Léo Valone, Emma Ferbera, Buzz Baum, Guillaume Salbreux, Guillaume Charras

Original languageEnglish
Article numbere2121868119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number26
DOIs
Accepted/In press28 Apr 2022
Published28 Jun 2022

Bibliographical note

Funding Information: We thank Susana Godinho (Queen Mary University of London, United Kingdom) for gateway cloning plasmids; Mathieu Coppey (Institut Curie, Paris, France) for advice on optogenetics and sharing reagents; Ayad Eddaoudi (University College London, Institute for Child Health) for flow cytometry analysis; Jonathan Fouchard, Julia Duque, Kazunori Yamamoto, and Diana Khoromskaia for comments and discussions; and members of the G.C. and B.B. laboratories for discussions. M.K. was supported by a Swiss National Science Foundation early postdoctoral fellowship (P2LAP3_164919) and by a European Research Council consolidator grant (CoG-647186) to G.C. P.B. was supported by a Cancer Research UK multidisciplinary award (C55977/A23342) to G.C. and G.S. M.B.S. and G.S. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317). Funding Information: Eddaoudi (University College London, Institute for Child Health) for flow cytometry analysis; Jonathan Fouchard, Julia Duque, Kazunori Yamamoto, and Diana Khoromskaia for comments and discussions; and members of the G.C. and B.B. laboratories for discussions. M.K. was supported by a Swiss National Science Foundation early postdoctoral fellowship (P2LAP3_164919) and by a European Research Council consolidator grant (CoG-647186) to G.C. P.B. was supported by a Cancer Research UK multidisciplinary award (C55977/A23342) to G.C. and G.S. M.B.S. and G.S. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317). Publisher Copyright: Copyright © 2022 the Author(s).

King's Authors

Abstract

Proper orientation of the mitotic spindle plays a crucial role in embryos, during tissue development, and in adults, where it functions to dissipate mechanical stress to maintain tissue integrity and homeostasis. While mitotic spindles have been shown to reorient in response to external mechanical stresses, the subcellular cues that mediate spindle reorientation remain unclear. Here, we used a combination of optogenetics and computational modeling to investigate how mitotic spindles respond to inhomogeneous tension within the actomyosin cortex. Strikingly, we found that the optogenetic activation of RhoA only influences spindle orientation when it is induced at both poles of the cell. Under these conditions, the sudden local increase in cortical tension induced by RhoA activation reduces pulling forces exerted by cortical regulators on astral microtubules. This leads to a perturbation of the balance of torques exerted on the spindle, which causes it to rotate. Thus, spindle rotation in response to mechanical stress is an emergent phenomenon arising from the interaction between the spindle positioning machinery and the cell cortex.

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