Modeling reveals cortical dynein-dependent fluctuations in bipolar spindle length

Mercadante, Dayna; Manning, Amity L.; Olson, Sarah D.

doi:10.1016/j.bpj.2021.05.030

Cited by 4 publications

(15 citation statements)

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“…Work from our group and others has implicated cortical dynein as a dominant driver of centrosome movement during mitosis in cells with two centrosomes (di Pietro et al, 2016; Mercadante et al, 2021). To test whether cortical dynein-driven centrosome movement is involved in centrosome clustering in cells with centrosome amplification, we perturbed dynein localization or function in cells with experimentally induced centrosome amplification.…”

Section: Resultsmentioning

confidence: 99%

“…Two complementary approaches were used to induce centrosome amplification: overexpression of PLK4 (indPLK4) to induce the biogenesis of extra centrosomes (Godinho et al, 2009) or induction of cytokinesis failure, as described above (Supplemental Figure S2 A,C). Next, cortical dynein motor activity was disrupted using the small molecule inhibitor dynarrestin (Hoing et al, 2018; Mercadante et al, 2021), or dynein localization was perturbed via siRNA-mediated depletion of Afadin or LGN (B,D). Individual cells were analyzed for centrosome number, centrosome location, and spindle structure, where clustering was assessed pre-anaphase and bipolar spindles were considered as those in which one or both spindle poles contained two or more centrosomes located within 5 μ m of each other (Figure 2 A,B).…”

Section: Resultsmentioning

confidence: 99%

“…In this work, we optimize and expand upon our previously described two-dimensional model with dynamic microtubules and stochastic motor-dependent force generation to capture the centrosome movement in cells with centrosome amplification (Mercadante et al, 2021). We allow microtubule-motor protein interactions with Eg5 and HSET on antiparallel microtubules, capturing the dominant roles of these proteins in mitosis.…”

Section: Modelingmentioning

confidence: 99%

“…All parameters were optimized to match experimental results. Additionally, all parameters that were modified from our previous publication (Mercadante et al, 2021) were re-tested in simulations with two centrosomes and asymmetric dynein localization to confirm that appropriate bipolar spindle length and dynamics were maintained (Supplemental Figure S8).…”

Section: Motor-dependent Force Generation and Centrosome Movementmentioning

confidence: 99%

“…Dynein is the major minus-end directed motor protein in the cell and has many functions. Throughout mitosis, dynein is localized at the kinetochore on chromosomes where it contributes to chromosome movement and alignment (Bader and Vaughan, 2010), at the spindle-poles where it actively sustains focusing of microtubule minus ends at centrosomes (Merdes et al, 2000), and at the cell cortex, where it contributes to centrosome movement and thus impacts bipolar spindle length, orientation, and positioning (Busson et al, 1998; O’Connell and Wang, 2000; Kiyomitsu and Cheeseman, 2012; di Pietro et al, 2016; Okumura et al, 2018; Mercadante et al, 2021). Dynein and its binding partner dynactin are anchored at the cell cortex by a complex including the proteins LGN, Afadin, and NuMA (Du and Macara, 2004; Kiyomitsu and Cheeseman, 2012; Kotak et al, 2012, 2013; di Pietro et al, 2016; Okumura et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

Mercadante

Aaron

Olson

et al. 2022

Preprint

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During cell division, the microtubule nucleating and organizing organelle, known as the centrosome, is critical for the formation of the mitotic spindle. In cells with two centrosomes, each centrosome functions as an anchor point for microtubules, leading to the formation of a bipolar spindle and progression through a bipolar cell division. When extra centrosomes are present, multipolar spindles form and the parent cell may divide into more than two daughter cells. Cells that are born from multipolar divisions are not viable and hence clustering of extra centrosomes and progression to a bipolar division are critical determinants of viability in cells with extra centrosomes. We combine experimental approaches with computational modeling to define a role for cortical dynein in centrosome clustering. We show that centrosome clustering fails and multipolar spindles dominate when cortical dynein distribution or activity is experimentally perturbed. Our simulations further reveal that centrosome clustering is sensitive to the distribution of dynein on the cortex. Together, these results indicate that dynein's cortical localization alone is insufficient for effective centrosome clustering and instead, dynamic relocalization of dynein from one side of the cell to the other throughout mitosis promotes timely clustering and bipolar cell division in cells with extra centrosomes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Modelingmentioning

confidence: 99%

Section: Motor-dependent Force Generation and Centrosome Movementmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

Mercadante

Aaron

Olson

et al. 2022

Preprint

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Positioning centrioles and centrosomes

Hannaford,

Rusan

2024

Journal of Cell Biology

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Centrosomes are the primary microtubule organizer in eukaryotic cells. In addition to shaping the intracellular microtubule network and the mitotic spindle, centrosomes are responsible for positioning cilia and flagella. To fulfill these diverse functions, centrosomes must be properly located within cells, which requires that they undergo intracellular transport. Importantly, centrosome mispositioning has been linked to ciliopathies, cancer, and infertility. The mechanisms by which centrosomes migrate are diverse and context dependent. In many cells, centrosomes move via indirect motor transport, whereby centrosomal microtubules engage anchored motor proteins that exert forces on those microtubules, resulting in centrosome movement. However, in some cases, centrosomes move via direct motor transport, whereby the centrosome or centriole functions as cargo that directly binds molecular motors which then walk on stationary microtubules. In this review, we summarize the mechanisms of centrosome motility and the consequences of centrosome mispositioning and identify key questions that remain to be addressed.

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Cortical dynein drives centrosome clustering in cells with centrosome amplification

Mercadante

Aaron

Olson

et al. 2023

MBoC

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During cell division, the microtubule nucleating and organizing organelle, known as the centrosome, is a critical component of the mitotic spindle. In cells with two centrosomes, each centrosome functions as an anchor point for microtubules, leading to the formation of a bipolar spindle and progression through a bipolar cell division. When extra centrosomes are present, multipolar spindles form and the parent cell may divide into more than two daughter cells. Cells that are born from multipolar divisions are not viable and hence clustering of extra centrosomes and progression to a bipolar division are critical determinants of viability in cells with extra centrosomes. We combine experimental approaches with computational modeling to define a role for cortical dynein in centrosome clustering. We show that centrosome clustering fails and multipolar spindles dominate when cortical dynein distribution or activity is experimentally perturbed. Our simulations further reveal that centrosome clustering is sensitive to the distribution of dynein on the cortex. Together, these results indicate that dynein's cortical localization alone is insufficient for effective centrosome clustering and instead, dynamic relocalization of dynein from one side of the cell to the other throughout mitosis promotes timely clustering and bipolar cell division in cells with extra centrosomes.

show abstract

Modeling reveals cortical dynein-dependent fluctuations in bipolar spindle length

Cited by 4 publications

References 130 publications

Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

Positioning centrioles and centrosomes

Cortical dynein drives centrosome clustering in cells with centrosome amplification

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