Epithelial spindle orientation diversities and uncertainties: recent developments and lingering questions

Seldin, Lindsey; Macara, Ian G.

doi:10.12688/f1000research.11370.1

Cited by 32 publications

(32 citation statements)

References 58 publications

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“…However the resolution of imaging in three dimensions was insufficient to build a quantitative picture of the outcome of these events. Nevertheless, in line with previous reports [23], we can detect no spindle orientation checkpoint as oriented and misoriented divisions proceed at the same rate in our live imaging experiments. This inability for cells to correct misoriented divisions highlights the importance of correctly establishing polarity prior to entry into mitosis.…”

Section: The Cask-dlg1 Interaction Is Required For Localisation Of Thsupporting

confidence: 93%

“…Spindle orientation requires a conserved set of proteins including LGN, which is normally localised to the basolateral membrane in epithelial cells. LGN localisation to the membrane is mediated in part by Gαi binding, but additional factors are also required for correct LGN localisation and function [23]. We therefore tested whether LGN localisation was affected by depletion of CASK.…”

Section: The Cask-dlg1 Interaction Is Required For Localisation Of Thmentioning

confidence: 99%

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The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

Porter

White

Mack

et al. 2018

Preprint

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Oriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for oriented cell division in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. Here we show that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions, and for normal lumen formation in 3D culture. We demonstrate that CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, and thereby identify a new cellular function for CASK. We show that depletion of CASK leads to misoriented divisions in 3D, and to the formation of multilumen structures in cultured kidney and breast epithelial cells. Blocking the direct interaction between CASK and Dlg1 with an interfering peptide disrupts spindle orientation and causes multilumen formation. We further show that the Dlg1-CASK interaction is important for the membrane localisation of the canonical LGN-NuMA complex, required for attachment of the mitotic spindle to the membrane and its correct positioning, as well as for astral microtubule stability. Together these results establish the importance of the CASK-Dlg1 interaction in oriented cell division and epithelial integrity.

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Section: The Cask-dlg1 Interaction Is Required For Localisation Of Thsupporting

confidence: 93%

Section: The Cask-dlg1 Interaction Is Required For Localisation Of Thmentioning

confidence: 99%

The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

Porter

White

Mack

et al. 2018

Preprint

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“…Contrasting the established role of Par3 in spindle orientation in several developmental systems 4,11,36,37 , our data indicate that polarity proteins help maintain adult tissue homeostasis primarily by controlling keratinocyte mechanics and thereby mitotic fidelity and genome integrity, rather than by sole orientation of mitotic spindles. Considering our new findings, it is tempting to speculate that, next to causing mitotic errors and DNA-damage triggered differentiation, disturbed cortical contractility also elicits the observed spindle orientation defects, e.g.…”

Section: Discussioncontrasting

confidence: 80%

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

Gomes

Letzian

Saynisch

et al. 2018

Preprint

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Epithelial homeostasis requires balanced progenitor cell proliferation and differentiation, whereas disrupting this equilibrium fosters degeneration or cancer. Here we studied how cell polarity signaling orchestrates epidermal self-renewal and differentiation. Using genetic ablation, quantitative imaging, mechanochemical reconstitution and atomic force microscopy, we find that mammalian Par3 couples genome integrity and epidermal fate through shaping keratinocyte mechanics, rather than mitotic spindle orientation. Par3 inactivation impairs actomyosin contractility and viscoelasticity, and elicits mitotic failures that trigger aneuploidy, mitosisdependent DNA damage responses, p53 stabilization and premature differentiation. Importantly, reconstituting myosin activity is sufficient to restore mitotic fidelity, genome integrity, and balanced differentiation and stratification. Collectively, this study deciphers a mechanical signaling network in which Par3 acts upstream of Rho/ROCK-mediated actomyosin contractility to promote intrinsic force generation, thereby maintaining mitotic accuracy and cellular fitness at the genomic level. Disturbing this network may compromise not only epidermal homeostasis but potentially also that of other self-renewing epithelia.

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“…Polarity plays a significant role in the regulation of symmetric and asymmetric divisions [ 176 , 185 , 186 , 187 ]. For example, the position of a cortical progenitor relative to the apical polar membrane in the cortex affects whether the cell undergoes symmetric or asymmetric division [ 180 , 188 , 189 ].…”

Section: Wnt and Cell Cyclementioning

confidence: 99%

Wnt Signaling and Its Impact on Mitochondrial and Cell Cycle Dynamics in Pluripotent Stem Cells

Rasmussen

Ortolano

Romero-Morales

et al. 2018

Genes

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The core transcriptional network regulating stem cell self-renewal and pluripotency remains an intense area of research. Increasing evidence indicates that modified regulation of basic cellular processes such as mitochondrial dynamics, apoptosis, and cell cycle are also essential for pluripotent stem cell identity and fate decisions. Here, we review evidence for Wnt regulation of pluripotency and self-renewal, and its connections to emerging features of pluripotent stem cells, including (1) increased mitochondrial fragmentation, (2) increased sensitivity to cell death, and (3) shortened cell cycle. We provide a general overview of the stem cell–specific mechanisms involved in the maintenance of these uncharacterized hallmarks of pluripotency and highlight potential links to the Wnt signaling pathway. Given the physiological importance of stem cells and their enormous potential for regenerative medicine, understanding fundamental mechanisms mediating the crosstalk between Wnt, organelle-dynamics, apoptosis, and cell cycle will be crucial to gain insight into the regulation of stemness.

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Epithelial spindle orientation diversities and uncertainties: recent developments and lingering questions

Cited by 32 publications

References 58 publications

The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

Wnt Signaling and Its Impact on Mitochondrial and Cell Cycle Dynamics in Pluripotent Stem Cells

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