An asymmetric junctional mechanoresponse coordinates mitotic rounding with epithelial integrity

Monster, Jooske L.; Donker, Lisa; Vliem, Marjolein J.; Win, Zaw; Matthews, Helen K.; Cheah, Joleen S.; Yamada, Sōichiro; Rooij, Johan de; Baum, Buzz; Gloerich, Martijn

doi:10.1083/jcb.202001042

Cited by 23 publications

(15 citation statements)

References 73 publications

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“…We also provide direct evidence that large epithelial rupture can arise by intercellular detachment during cell division, which provides a weak spot primed for disruption upon increased mechanical stress. This is consistent with previous observations that reinforcement of junctional attachment to the cytoskeleton prevents detachment during cell division in the Drosophila embryonic epithelium and mammalian cell culture [68, 69]. Dividing cells do not generate gaps upon aPKC inactivation in a mosaic tissue, showing that a direct effect in mitotic cells is not responsible for gap formation by itself.…”

Section: Discussionsupporting

confidence: 92%

Apical constriction induces tissue rupture in a proliferative epithelium

Osswald

Barros-Carvalho

Carmo

et al. 2022

Preprint

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Apical-basal polarity is an essential epithelial trait controlled by the evolutionarily conserved PAR-aPKC polarity network. Deregulation of polarity proteins disrupts tissue organization during development and in disease, but the underlying mechanisms are unclear due to the broad implications of polarity loss. Here, we uncovered how Drosophila aPKC maintains epithelial architecture by directly observing tissue disorganization after fast optogenetic inactivation in living adult flies and ovaries cultured ex vivo. We show that fast aPKC perturbation in the proliferative follicular epithelium produces large epithelial gaps that result from increased apical constriction, rather than loss of apical-basal polarity. Accordingly, we could modulate the incidence of epithelial gaps by increasing and decreasing actomyosin-driven contractility. We traced the origin of epithelial gaps to tissue rupture next to dividing cells. Live imaging shows that aPKC perturbation rapidly induces apical constriction in non-mitotic cells, producing pulling forces that ultimately detach dividing and neighbouring cells. We further demonstrate that epithelial rupture requires a global increase of apical constriction, since it was prevented by the presence of non-constricting cells. Conversely, a global induction of apical tension through light-induced recruitment of RhoGEF2 to the apical side was sufficient to produce tissue rupture. Hence, our work reveals that the roles of aPKC in polarity and actomyosin regulation are separable and provides the first in vivo evidence that excessive tissue stress can break the epithelial barrier during proliferation.

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Section: Discussionsupporting

confidence: 92%

Apical constriction induces tissue rupture in a proliferative epithelium

Osswald

Barros-Carvalho

Carmo

et al. 2022

Preprint

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“…The area ( A ) and the perimeter ( P ) of the cell were measured in Fiji ImageJ, and the circularity ( C ) was calculated using the following equation: C = 4π × A / P 2 (ref. 76 ). At least ten cells of each cell line were measured.…”

Section: Methodsmentioning

confidence: 99%

CDK1–cyclin-B1-induced kindlin degradation drives focal adhesion disassembly at mitotic entry

2022

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The disassembly of integrin-containing focal adhesions (FAs) at mitotic entry is essential for cell rounding, mitotic retraction fibre formation, bipolar spindle positioning and chromosome segregation. The mechanism that drives FA disassembly at mitotic entry is unknown. Here, we show that the CDK1–cyclin B1 complex phosphorylates the integrin activator kindlin, which results in the recruitment of the cullin 9–FBXL10 ubiquitin ligase complex that mediates kindlin ubiquitination and degradation. This molecular pathway is essential for FA disassembly and cell rounding, as phospho-inhibitory mutations of the CDK1 motif prevent kindlin degradation, FA disassembly and mitotic cell rounding. Conversely, phospho-mimetic mutations promote kindlin degradation in interphase, accelerate mitotic cell rounding and impair mitotic retraction fibre formation. Despite the opposing effects on kindlin stability, both types of mutations cause severe mitotic spindle defects, apoptosis and aneuploidy. Thus, the exquisite regulation of kindlin levels at mitotic entry is essential for cells to progress accurately through mitosis.

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“…Recent work in cell culture models showed that vinculin can be recruited asymmetrically in a force-dependent manner at sites of cadherin adhesion near mitotic cells. Whilst in this case, asymmetric recruitment promotes cell shape changes during cell division and maintenance of epithelial integrity (Monster et al, 2021), our study reveals that asymmetric vinculin requirements at cell junctions can also regulate cell fate decisions and tissue composition in the intestine. Our findings place vinculin in a feedback loop that couples the process of enterocyte differentiation to stem cell proliferation in the intestine.…”

Section: Discussionmentioning

confidence: 86%

Vinculin recruitment to α-catenin halts the differentiation and maturation of enterocyte progenitors to maintain homeostasis of the Drosophila intestine

Bohère

Eldridge-Thomas

Kolahgar

2021

Preprint

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Mechanisms communicating changes in tissue stiffness and size are particularly relevant in the intestine, because it is subject to constant mechanical stresses caused by peristalsis of its variable content. Using the Drosophila intestinal epithelium, we investigate the role of vinculin, one of the best characterised mechanoeffectors, which functions in both cadherin and integrin adhesion complexes. We discovered that vinculin regulates cell fate decisions, by preventing precocious activation and differentiation of intestinal progenitors into absorptive cells. It achieves this in concert with α-catenin at sites of cadherin adhesion, rather than as part of integrin function. Following asymmetric division of the stem cell into a stem cell and an enteroblast, the two cells initially remain connected by adherens junctions, where vinculin is required, only on the enteroblast side, to maintain the enteroblast in a quiescent state and inhibit further divisions of the stem cell. Removing vinculin increases enteroblast differentiation and numbers, resulting in an enlarged gut with improved ability to recover after starvation. Thus, mechanical regulation at the contact between stem cells and their progeny is used to control tissue cell number.

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An asymmetric junctional mechanoresponse coordinates mitotic rounding with epithelial integrity

Cited by 23 publications

References 73 publications

Apical constriction induces tissue rupture in a proliferative epithelium

Apical constriction induces tissue rupture in a proliferative epithelium

CDK1–cyclin-B1-induced kindlin degradation drives focal adhesion disassembly at mitotic entry

Vinculin recruitment to α-catenin halts the differentiation and maturation of enterocyte progenitors to maintain homeostasis of the Drosophila intestine

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