Intercentrosomal angular separation during mitosis plays a crucial role for maintaining spindle stability

Sutradhar, Sabyasachi; Basu, Santanu Kumar; Paul, Raja

doi:10.1103/physreve.92.042714

“…Further, we find that for sufficiently small kinetochore-MT interaction strength, both bipolar spindle structure and monopolar structure (with zero separation distance between centrosomes) are stable as has been observed in numerical studies of Ref. [3,4]. We also find a regime of bistability of spindle assembly for certain parameter range wherein the spindle can be stable for two different finite separation distance between centrosomes.…”

supporting

confidence: 78%

“…During mitotic cell division, the two centrosomes within the cell serves as the poles and nucleating sites for microtubules (MTs). The polymerizing MTs from the opposite centrosomes overlap, leading to the formation of spindle structure during metaphase [1][2][3][4] (see Fig. 1).…”

mentioning

confidence: 99%

Mechanical stability of bipolar spindle assembly

Malgaretti

¹

,

Muhuri

²

2016

EPL

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Assembly and stability of mitotic spindle is governed by the interplay of various intra-cellular forces, e.g. the forces generated by motor proteins by sliding overlapping anti-parallel microtubules (MTs) polymerized from the opposite centrosomes, the interaction of kinetochores with MTs, and the interaction of MTs with the chromosomes arms. We study the mechanical behavior and stability of spindle assembly within the framework of a minimal model which includes all these effects. For this model, we derive a closed-form analytical expression for the force acting between the centrosomes as a function of their separation distance and we show that an effective potential can be associated with the interactions at play. We obtain the stability diagram of spindle formation in terms of parameters characterizing the strength of motor sliding, repulsive forces generated by polymerizing MTs, and the forces arising out of interaction of MTs with kinetochores. The stability diagram helps in quantifying the relative effects of the different interactions and elucidates the role of motor proteins in formation and inhibition of spindle structures during mitotic cell division. We also predict a regime of bistability for certain parameter range, wherein the spindle structure can be stable for two different finite separation distances between centrosomes. This occurrence of bistability also suggests mechanical versatility of such self-assembled spindle structures.

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“…1). Using conventional assumptions of a large number of isotropically distributed MTs (19,(41)(42)(43), we introduce the expressions for f CS−CS , and for respective potential energy of moving one CS from distance r 1 to r 2 away from another CS: Here f (0) CS−CS is the force between a pair of proximal CSs, r is the distance between CSs and L 1 is the spatial range of the force. Here we utilize one of the most simple and frequently used exponentially decreasing spatial dependence of the force; in the Supporting Information we explore other spatial dependencies.…”

Section: Methodsmentioning

confidence: 99%

Mechanics of Multicentrosomal Clustering in Bipolar Mitotic Spindles

Chatterjee

¹

,

Sarkar

²

,

Zhu

³

et al. 2020

Biophysical Journal

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To segregate chromosomes in mitosis, cells assemble mitotic spindle, a molecular machine with centrosomes at two opposing cell poles and chromosomes at the equator. Microtubules and molecular motors connect the poles to kinetochores, specialized protein assemblies on the centromere regions of the chromosomes. Bipolarity of the spindle is crucial for the proper cell division, and two centrosomes in animal cells naturally become two spindle poles. Cancer cells are often multi-centrosomal, yet they are able to assemble bipolar spindles by clustering centrosomes into two spindle poles. Mechanisms of this clustering are debated. In this study, we computationally screen effective forces between a) centrosomes, b) centrosomes and kinetochores, c) centrosomes and chromosome arms, d) centrosomes and cell cortex, to understand mechanics that determines three-dimensional spindle architecture. To do this, we use stochastic Monte Carlo search for stable mechanical equilibria in effective energy landscape of the spindle. We find that the following conditions have to be met to robustly assemble the bipolar spindle in a multi-centrosomal cell: 1) strengths of centrosomes' attraction to each other and to the cell cortex have to be proportional to each other; 2) strengths of centrosomes' attraction to kinetochores and repulsion from the chromosome arms have to be proportional to each other. We also find that three other spindle configurations emerge if these conditions are not met: a) collapsed, b) monopolar, c) multipolar spindles, and the computational screen reveal mechanical conditions for these abnormal spindles. Running title: Multi-centrosomal clusteringSignificance statement: To segregate chromosomes, cells assemble bipolar mitotic spindle. Multiple mechanical forces generated by microtubules and molecular motors in the spindle govern the spindle architecture, but it is unclear what force balances support the bipolarity of the spindle. This problem is especially difficult and important in cancer cells, which often have multiple centrosomes that somehow are able to cluster into two spindle poles. By using stochastic energy minimization in an effective energy landscape of the spindle and computationally screening forces, we find mechanical conditions for mono-, multi-and bi-polar spindles. We predict how microtubule and motor parameters have to be regulated in mitosis in multi-centrosomal cells.

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“…1). Using conventional assumptions of a large number of isotropically distributed MTs (19,(41)(42)(43), we introduce the expressions for f CS−CS , and for respective potential energy of moving one CS from distance r 1 to r 2 away from another CS: In confinement of the cell volume, but without active interaction with the cortex, multipolar spindle emerges when CSs repel each other. (C) CSs aggregate into two clusters at the opposite cell poles, which chromosomes gather at the equator, creating bipolar spindle, when CSs are mutually attractive and also are attracted to the cell cortex ( f CS−C RT X ).…”

Section: Interactions Between Pairs Of Cssmentioning

confidence: 99%

Mechanics of multi-centrosomal clustering in bipolar mitotic spindles

Chatterjee

¹

,

Sarkar

²

,

Zhu

³

et al. 2019

Preprint

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To segregate chromosomes in mitosis, cells assemble mitotic spindle, a molecular machine with centrosomes at two opposing cell poles and chromosomes at the equator. Microtubules and molecular motors connect the poles to kinetochores, specialized protein assemblies on the centromere regions of the chromosomes. Bipolarity of the spindle is crucial for the proper cell division, and two centrosomes in animal cells naturally become two spindle poles. Cancer cells are often multi-centrosomal, yet they are able to assemble bipolar spindles by clustering centrosomes into two spindle poles. Mechanisms of this clustering are debated. In this study, we computationally screen effective forces between a) centrosomes, b) centrosomes and kinetochores, c) centrosomes and chromosome arms, d) centrosomes and cell cortex, to understand mechanics that determines three-dimensional spindle architecture. To do this, we use stochastic Monte Carlo search for stable mechanical equilibria in effective energy landscape of the spindle. We find that the following conditions have to be met to robustly assemble the bipolar spindle in a multi-centrosomal cell: 1) strengths of centrosomes' attraction to each other and to the cell cortex have to be proportional to each other; 2) strengths of centrosomes' attraction to kinetochores and repulsion from the chromosome arms have to be proportional to each other. We also find that three other spindle configurations emerge if these conditions are not met: a) collapsed, b) monopolar, c) multipolar spindles, and the computational screen reveal mechanical conditions for these abnormal spindles. Running title: Multi-centrosomal clusteringSignificance statement: To segregate chromosomes, cells assemble bipolar mitotic spindle. Multiple mechanical forces generated by microtubules and molecular motors in the spindle govern the spindle architecture, but it is unclear what force balances support the bipolarity of the spindle. This problem is especially difficult and important in cancer cells, which often have multiple centrosomes that somehow are able to cluster into two spindle poles. By using stochastic energy minimization in an effective energy landscape of the spindle and computationally screening forces, we find mechanical conditions for mono-, multi-and bi-polar spindles. We predict how microtubule and motor parameters have to be regulated in mitosis in multi-centrosomal cells.

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Intercentrosomal angular separation during mitosis plays a crucial role for maintaining spindle stability

Cited by 8 publications

References 80 publications

Mechanical stability of bipolar spindle assembly

Mechanical stability of bipolar spindle assembly

Mechanics of Multicentrosomal Clustering in Bipolar Mitotic Spindles

Mechanics of multi-centrosomal clustering in bipolar mitotic spindles

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