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Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

Suresh, Pooja and Galstyan, Vahe and Phillips, Rob and Dumont, Sophie (2022) Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220412-265586000

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Abstract

During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We previously developed microneedle manipulation to mechanically challenge k-fiber anchorage, and observed spatially distinct response features revealing the presence of heterogeneous anchorage (Suresh et al. 2020). How anchorage is precisely spatially regulated, and what forces are necessary and sufficient to recapitulate the k-fiber’s response to force remain unclear. Here, we develop a coarse-grained k-fiber model and combine with manipulation experiments to infer underlying anchorage using shape analysis. By systematically testing different anchorage schemes, we find that forces solely at k-fiber ends are sufficient to recapitulate unmanipulated k-fiber shapes, but not manipulated ones for which lateral anchorage over a 3 μm length scale near chromosomes is also essential. Such anchorage robustly preserves k-fiber orientation near chromosomes while allowing pivoting around poles. Anchorage over a shorter length scale cannot robustly restrict pivoting near chromosomes, while anchorage throughout the spindle obstructs pivoting at poles. Together, this work reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle, which we propose are key for function.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.04.08.487649DOIDiscussion Paper
https://resolver.caltech.edu/CaltechAUTHORS:20221128-494241100.20Related ItemPublished Version
ORCID:
AuthorORCID
Suresh, Pooja0000-0002-7793-4827
Galstyan, Vahe0000-0001-7073-9175
Phillips, Rob0000-0003-3082-2809
Dumont, Sophie0000-0002-8283-1523
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. We thank Alexey Khodjakov for PtK2 GFP-α-tubulin cells and Timothy Mitchison for FCPT. We are grateful to Nenad Pavin for helpful discussions, and Arthur Molines, Soichi Hirokawa, Miquel Rosas Salvans, Lila Neahring, Caleb Rux, Gabe Salmon, and other members of the Phillips and Dumont Labs for critical feedback on our work. This work was supported by NIH 1R01GM134132, NIH R35GM136420, NSF CAREER 1554139, NSF 1548297 Center for Cellular Construction, NIH 2R35GM118043-06, the John Templeton Foundation 51250 and 60973 (R.P.), the Chan Zuckerberg Biohub (S.D. and R.P.), NSF Graduate Research Fellowship and a UCSF Kozloff Fellowship (P.S.). The authors have declared no competing interest.
Funders:
Funding AgencyGrant Number
NIH1R01GM134132
NIHR35GM136420
NSFCMMI-1554139
NSFDBI-1548297
NIH2R35GM118043-06
John Templeton Foundation51250
John Templeton Foundation60973
Chan-Zuckerberg BiohubUNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
University of California, San FranciscoUNSPECIFIED
DOI:10.1101/2022.04.08.487649
Record Number:CaltechAUTHORS:20220412-265586000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220412-265586000
Official Citation:Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle Pooja Suresh, Vahe Galstyan, Rob Phillips, Sophie Dumont bioRxiv 2022.04.08.487649; doi: https://doi.org/10.1101/2022.04.08.487649
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114243
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Apr 2022 19:43
Last Modified:08 Dec 2022 01:37

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