The Chirality of the Mitotic Spindle Provides a Mechanical Response to Forces and Depends on Microtubule Motors and Crosslinkers

Trupinić, Monika; Kokanović, Barbara; Ponjavić, Ivana; Barišić, Ivan; Šegvić, Siniša; Ivec, Arian; Tolić, Iva M.

doi:10.2139/ssrn.3931649

Cited by 3 publications

(4 citation statements)

References 46 publications

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“…The k-fiber’s connection (anchorage) to the spindle is mediated by a dense mesh-like network of non-kinetochore microtubules (non-kMTs) which connect to k-fibers along their length (Mastronarde et al 1993, O’Toole et al 2020) via both motor and non-motor proteins. Although this network cannot be easily visualized with light microscopy, physical perturbations such as laser ablation (Kajtez et al 2016, Milas and Tolić 2016, Elting et al 2017) and cell compression (Trupinić et al 2020, Neahring et al 2021) have been instrumental in uncovering how this network anchors k-fibers. The non-kMT network bears mechanical load locally (Milas and Tolić 2016, Elting et al 2017), links sister k-fibers together (Kajtez et al 2016), and contributes to k-fiber and spindle chirality (Trupinić et al 2020, Neahring et al 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Although this network cannot be easily visualized with light microscopy, physical perturbations such as laser ablation (Kajtez et al 2016, Milas and Tolić 2016, Elting et al 2017) and cell compression (Trupinić et al 2020, Neahring et al 2021) have been instrumental in uncovering how this network anchors k-fibers. The non-kMT network bears mechanical load locally (Milas and Tolić 2016, Elting et al 2017), links sister k-fibers together (Kajtez et al 2016), and contributes to k-fiber and spindle chirality (Trupinić et al 2020, Neahring et al 2021). Recent advances in microneedle manipulation enabled us to mechanically challenge k-fiber anchorage with unprecedented spatiotemporal control (Long et al 2020, Suresh et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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

Suresh

Galstyan

Phillips

et al. 2022

Preprint

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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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Suresh

Galstyan

Phillips

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The k-fiber's connection (anchorage) to the spindle is mediated by a dense mesh-like network of non-kinetochore microtubules (non-kMTs) which connect to k-fibers along their length (Mastronarde et al 1993, O'Toole et al 2020) via both motor and non-motor proteins. Although this network cannot be easily visualized with light microscopy, physical perturbations such as laser ablation (Kajtez et al 2016, Elting et al 2017) and cell compression (Trupinić et al 2020, Neahring et al 2021) have been instrumental in uncovering how this network anchors k-fibers. The non-kMT network bears mechanical load locally Tolić 2016, Elting et al 2017), links sister k-fibers together (Kajtez et al 2016), and contributes to k-fiber and spindle chirality (Trupinić et al 2020, Neahring et al 2021.…”

Section: Introductionmentioning

confidence: 99%

“…Although this network cannot be easily visualized with light microscopy, physical perturbations such as laser ablation (Kajtez et al 2016, Elting et al 2017) and cell compression (Trupinić et al 2020, Neahring et al 2021) have been instrumental in uncovering how this network anchors k-fibers. The non-kMT network bears mechanical load locally Tolić 2016, Elting et al 2017), links sister k-fibers together (Kajtez et al 2016), and contributes to k-fiber and spindle chirality (Trupinić et al 2020, Neahring et al 2021. Recent advances in microneedle manipulation enabled us to mechanically challenge k-fiber anchorage with unprecedented spatiotemporal control (Long et al 2020.…”

Section: Introductionmentioning

confidence: 99%

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

Suresh¹,

Galstyan²,

Phillips³

et al. 2022

Preprint

View full text Add to dashboard Cite

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 ). 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.

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Human kinesin-5 KIF11 drives the helical motion of anti-parallel and parallel microtubules around each other

Meißner,

Schüring,

Mitra

et al. 2023

Preprint

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During mitosis, motor proteins and microtubule-associated protein organize the spindle apparatus by cross-linking and sliding microtubules. Kinesin-5 plays a vital role in spindle formation and maintenance, potentially inducing twist in the spindle fibers. The off-axis power stroke of kinesin-5 could generate this twist, but its implications in microtubule organization remain unclear. Here, we investigate 3D microtubule-microtubule sliding mediated by the human kinesin-5, KIF11, and found that the motor caused right-handed rotation of anti-parallel microtubules around each other. The effective sidestepping probability of KIF11 increased with reduced ATP concentration, indicating that forward and sideways stepping of the motor are not strictly coupled. Further, the microtubule-microtubule distance (motor extension) during sliding decreased with increasing sliding velocity. Intriguingly, parallel microtubules cross-linked by KIF11 orbit without forward motion, with nearly full extension. Altering the length of the neck linker increased the forward velocity and pitch of microtubules in anti-parallel overlaps. Taken together, we suggest that helical motion and orbiting of microtubules, driven by KIF11, enable flexible and context-dependent filament organization, as well as torque regulation within the mitotic spindle.

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The Chirality of the Mitotic Spindle Provides a Mechanical Response to Forces and Depends on Microtubule Motors and Crosslinkers

Cited by 3 publications

References 46 publications

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

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

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

Human kinesin-5 KIF11 drives the helical motion of anti-parallel and parallel microtubules around each other

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