Coupling changes in cell shape to chromosome segregation

Ramkumar, Nitya; Baum, Buzz

doi:10.1038/nrm.2016.75

Cited by 124 publications

(141 citation statements)

References 149 publications

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“…S5 C and D). The tension-sensitive junctional localization of LGN before mitotic entry indicates that the recruitment of LGN to cell-cell contacts is uncoupled from putative mechanical changes due to mitotic rounding (54). Of note, NuMA may translate not only cell-cell junctional tension but also interphase cell shape to the orientation of the mitotic spindle, as shown for its Drosophila homolog Mud, albeit in an LGN-independent manner (45).…”

Section: Discussionmentioning

confidence: 99%

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

Hart

Tan

Siemers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin-Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell-cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of Ecadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of trans engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions.cell-cell adhesion | cell division orientation | mitotic spindle | mechanotransduction

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Section: Discussionmentioning

confidence: 99%

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

Hart

Tan

Siemers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Epithelial expansion driven by cell proliferation is a key feature throughout development, and occurs in hyperplasia, a precursor to cancer. Cell divisions during development must occur robustly, as mis-segregation of chromosomes leads to severe genetic abnormalities such as aneuploidy [4]. Over 90% of human tumors are derived from epithelia [5], and the accumulation of genetic errors during cell division can lead to all of the hallmarks of cancer [6].…”

Section: Introductionmentioning

confidence: 99%

“…MR occurs in detached cells, cells adherent to a substrate as well as in epithelial cells within tissues [10–12]. MR in epithelia coincides with an increased polymerization of actomyosin at the cell cortex, which results in an increase in cortical stiffness [4,11]. Simultaneously, the intracellular pressure increases [11], and cells partially reduce adhesion to their neighbors and the substrate [4].…”

Section: Introductionmentioning

confidence: 99%

Multi-scale computational study of the mechanical regulation of cell mitotic rounding in epithelia

et al. 2017

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Mitotic rounding during cell division is critical for preventing daughter cells from inheriting an abnormal number of chromosomes, a condition that occurs frequently in cancer cells. Cells must significantly expand their apical area and transition from a polygonal to circular apical shape to achieve robust mitotic rounding in epithelial tissues, which is where most cancers initiate. However, how cells mechanically regulate robust mitotic rounding within packed tissues is unknown. Here, we analyze mitotic rounding using a newly developed multi-scale subcellular element computational model that is calibrated using experimental data. Novel biologically relevant features of the model include separate representations of the sub-cellular components including the apical membrane and cytoplasm of the cell at the tissue scale level as well as detailed description of cell properties during mitotic rounding. Regression analysis of predictive model simulation results reveals the relative contributions of osmotic pressure, cell-cell adhesion and cortical stiffness to mitotic rounding. Mitotic area expansion is largely driven by regulation of cytoplasmic pressure. Surprisingly, mitotic shape roundness within physiological ranges is most sensitive to variation in cell-cell adhesivity and stiffness. An understanding of how perturbed mechanical properties impact mitotic rounding has important potential implications on, amongst others, how tumors progressively become more genetically unstable due to increased chromosomal aneuploidy and more aggressive.

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“…In contrast, the repulsive term models the passive cytoskeleton interaction that occurs if cells are too close. This repulsive term also defines the forces generated after the cleavage on cell division …”

Section: Modelmentioning

confidence: 99%

A hybrid computational model to explore the topological characteristics of epithelial tissues

González-Valverde

García-Aznar

2017

Numer Methods Biomed Eng

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Epithelial tissues show a particular topology where cells resemble a polygon-like shape, but some biological processes can alter this tissue topology. During cell proliferation, mitotic cell dilation deforms the tissue and modifies the tissue topology. Additionally, cells are reorganized in the epithelial layer and these rearrangements also alter the polygon distribution. We present here a computer-based hybrid framework focused on the simulation of epithelial layer dynamics that combines discrete and continuum numerical models. In this framework, we consider topological and mechanical aspects of the epithelial tissue. Individual cells in the tissue are simulated by an off-lattice agent-based model, which keeps the information of each cell. In addition, we model the cell-cell interaction forces and the cell cycle. Otherwise, we simulate the passive mechanical behaviour of the cell monolayer using a material that approximates the mechanical properties of the cell. This continuum approach is solved by the finite element method, which uses a dynamic mesh generated by the triangulation of cell polygons. Forces generated by cell-cell interaction in the agent-based model are also applied on the finite element mesh. Cell movement in the agent-based model is driven by the displacements obtained from the deformed finite element mesh of the continuum mechanical approach. We successfully compare the results of our simulations with some experiments about the topology of proliferating epithelial tissues in Drosophila. Our framework is able to model the emergent behaviour of the cell monolayer that is due to local cell-cell interactions, which have a direct influence on the dynamics of the epithelial tissue.

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Coupling changes in cell shape to chromosome segregation

Cited by 124 publications

References 149 publications

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

Multi-scale computational study of the mechanical regulation of cell mitotic rounding in epithelia

A hybrid computational model to explore the topological characteristics of epithelial tissues

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