Microtubule pivoting enables mitotic spindle assembly in <i>S. cerevisiae</i>

Fong, Kimberly K.; Davis, Trisha N.; Asbury, Charles L.

doi:10.1083/jcb.202007193

Cited by 6 publications

(6 citation statements)

References 79 publications

(130 reference statements)

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“…Torques of unknown origin in the spindle generate chiral MT structures [Mit+20]. Pivoting movements of MTs in spindles also have been observed [Kal+13;Win+19;FDA21]. The idea of the progressive restriction of the angle between a MT and a kinetochore to which this MT binds proposed in [Ede+20] is similar to our idea of the CS-CH torque.…”

Section: Discussionsupporting

confidence: 64%

Mechanical torque promotes bipolarity of the mitotic spindle through multi-centrosomal clustering

Miles

Zhu

Mogilner

2021

Preprint

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Intracellular forces shape cellular organization and function. One example is the mi-totic spindle, a cellular machine consisting of multiple chromosomes and centrosomes which interact via dynamic microtubule filaments and motor proteins, resulting in complicated spatially dependent forces. For a cell to divide properly, is important for the spindle to be bipolar, with chromosomes at the center and multiple centrosomes clustered into two ‘poles’ at opposite sides of the chromosomes. Experimental observations show that in unhealthy cells, the spindle can take on a variety of patterns. What forces drive each of these patterns? It is known that attraction between centrosomes is key to bipolarity, but what the prevents the centrosomes from collapsing into a monopolar configuration? Here, we explore the hypothesis that torque rotating chromosome arms into orientations perpendicular to the centrosome-centromere vector promotes spindle bipolarity. To test this hypothesis, we construct a pairwise-interaction model of the spindle. On a continuum version of the model, an integro-PDE system, we perform linear stability analysis and construct numerical solutions which display a variety of spatial patterns. We also simulate a discrete particle model resulting in a phase diagram that confirms that the spindle bipolarity emerges most robustly with torque. Altogether, our results suggest that rotational forces may play an important role in dictating spindle patterning.

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Section: Discussionsupporting

confidence: 64%

Mechanical torque promotes bipolarity of the mitotic spindle through multi-centrosomal clustering

Miles

Zhu

Mogilner

2021

Preprint

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“…Even though not all species possess a centrosome, the pivoting capability is conserved, as in yeast microtubules pivot around the spindle pole body, the functional equivalent of the centrosome (Kalinina et al, 2013). Whereas passive thermal pivoting in yeast promotes kinetochore capture (Blackwell et al, 2017b; Cojoc et al, 2016; Kalinina et al, 2013), active motor-driven pivoting drives spindle assembly and movement into the bud (Baumgärtner and Tolić, 2014; Blackwell et al, 2017a; Fong et al, 2021; Winters et al, 2019). Our results show that in human cells, active pivoting is driven by Eg5-powered spindle elongation, while passive pivoting occurs at non-moving centrosomes.…”

Section: Discussionmentioning

confidence: 99%

Microtubule pivoting driven by spindle elongation rescues polar chromosomes to ensure faithful mitosis

Koprivec,

Štimac,

Mikec

et al. 2024

Preprint

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Polar chromosomes represent a subset of ∼7 chromosomes in human cells that first attach to the mitotic spindle behind the spindle pole. These chromosomes are delayed in congression to the metaphase plate and prone to segregation errors. Yet, their mechanism of congression remains elusive. By using stimulated emission depletion (STED) and lattice light-sheet (LLS) microscopy, here we show that polar chromosomes require a unique congression step to transit across the spindle pole. This step occurs independently of the known congression drivers, including CENP-E, kinetochore dynein, chromokinesins, and actomyosin. Instead, it relies on the pivoting of chromosome-carrying astral microtubules around the centrosome towards the spindle surface. During pivoting, polar chromosomes form complex attachments with astral microtubules that persist throughout the process. By altering the kinesin-5 Eg5/KIF11 activity to reverse, restore, or block spindle elongation, we show that spindle elongation drives the pivoting and dictates its direction and magnitude. We reveal impaired spindle elongation as a major cause of congression defects and segregation errors of polar chromosomes in RPE1 cells after Mps1 kinase inhibition, and in the high-grade serous ovarian carcinoma OVSAHO cells. Increasing spindle elongation efficiency by depleting the kinesin-4 KIF4A rescued polar chromosomes in OVSAHO cells, supporting the causal relationship between spindle elongation and resolution of polar chromosomes. We conclude that polar chromosomes depend on spindle elongation to propel the pivoting of their astral microtubules, enabling their contact with the spindle surface, congression, and proper segregation. In the context of disease, our findings suggest that altering spindle elongation has the potential to modify mitotic errors in certain cancer cells.

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“…However, the conditions of our reconstitution assay did not include the key role played by molecular motors that move the MTOC by pulling on microtubules (Yi et al , 2013) and by regulating their dynamics (Hooikaas et al , 2020) during cell polarization. Furthermore, our experimental conditions and the use of short pieces of MTs attached to a bead did not offer us the possibility to control MT pivoting around the aMTOC, a property that could have promoted symmetry break and amplified MTOC decentering (Baumgärtner & Tolić, 2014; Letort et al , 2016; Fong et al , 2021). In addition, we studied aMTOC positioning in response to the production of pushing forces in cylindrical and rigid microwells.…”

Section: Discussionmentioning

confidence: 99%

Actin network architecture can ensure robust centering or sensitive decentering of the centrosome

Yamamoto¹,

Gaillard²,

Vianay

et al. 2022

The EMBO Journal

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The orientation of cell polarity depends on the position of the centrosome, the main microtubule‐organizing center (MTOC). Microtubules (MTs) transmit pushing forces to the MTOC as they grow against the cell periphery. How the actin network regulates these forces remains unclear. Here, in a cell‐free assay, we used purified proteins to reconstitute the interaction of a microtubule aster with actin networks of various architectures in cell‐sized microwells. In the absence of actin filaments, MTOC positioning was highly sensitive to variations in microtubule length. The presence of a bulk actin network limited microtubule displacement, and MTOCs were held in place. In contrast, the assembly of a branched actin network along the well edges centered the MTOCs by maintaining an isotropic balance of pushing forces. An anisotropic peripheral actin network caused the MTOC to decenter by focusing the pushing forces. Overall, our results show that actin networks can limit the sensitivity of MTOC positioning to microtubule length and enforce robust MTOC centering or decentering depending on the isotropy of its architecture.

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Microtubule pivoting enables mitotic spindle assembly in S. cerevisiae

Cited by 6 publications

References 79 publications

Mechanical torque promotes bipolarity of the mitotic spindle through multi-centrosomal clustering

Mechanical torque promotes bipolarity of the mitotic spindle through multi-centrosomal clustering

Microtubule pivoting driven by spindle elongation rescues polar chromosomes to ensure faithful mitosis

Actin network architecture can ensure robust centering or sensitive decentering of the centrosome

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