Cell reintegration: Stray epithelial cells make their way home

Wilson, Tyler J.; Bergstralh, Daniel T.

doi:10.1002/bies.201600248

Cited by 9 publications

(9 citation statements)

References 49 publications

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“…Thus, it is possible that daughter cells could either differentiate following divisions or alternatively, reintegrate into the basal layer following mitosis. Such behaviors have been recently documented in other epithelia (McKinley et al, 2018; Wilson & Bergstralh, 2017), and dedifferentiation has been reported following wounding in adult skin (Donati et al, 2017). However, it has not been technically possible to follow daughter cell fates long term following cell division with ex vivo imaging of embryonic explants.…”

Section: Resultsmentioning

confidence: 65%

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Descovich

Lough

Jena

et al. 2022

Preprint

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Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically-polarized, evolutionarily-conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but little is known about the molecular regulation of planar divisions. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN, and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light into how spindle orientation influences epidermal stratification.

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Section: Resultsmentioning

confidence: 65%

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Descovich

Lough

Jena

et al. 2022

Preprint

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“…Cell reintegration is a relatively recently identified morphogenetic cell behaviour that appears to be a fundamental, conserved morphogenetic process [42]. Through live imaging and genetic studies in Drosophila epithelial tissues, it was shown that daughter cells born apically or basally displaced from a tissue layer are able to (re)integrate back into the layer [42,131]. The IgCAMs Nrg and Fas2 are regulators of cell reintegration in Drosophila epithelia [42].…”

Section: Reintegration (A) Neuroglian and Fasciclinmentioning

confidence: 99%

“…Cell reintegration is proposed to be driven by the energyfavourable tendency to maximize cell-cell adhesion along the lateral surface [42,131]. This model to explain reintegration can be pictured as 'zipping up', where the rapid expansion of cell-cell contact is driven by the formation of homophilic adhesions between IgCAM molecules, acting as the teeth of a zipper.…”

Section: Reintegration (A) Neuroglian and Fasciclinmentioning

confidence: 99%

Neuronal immunoglobulin superfamily cell adhesion molecules in epithelial morphogenesis: insights fromDrosophila

Finegan

Bergstralh

2020

Phil. Trans. R. Soc. B

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In this review, we address the function of immunoglobulin superfamily cell adhesion molecules (IgCAMs) in epithelia. Work in the Drosophila model system in particular has revealed novel roles for calcium-independent adhesion molecules in the morphogenesis of epithelial tissues. We review the molecular composition of lateral junctions with a focus on their IgCAM components and reconsider the functional roles of epithelial lateral junctions. The epithelial IgCAMs discussed in this review have well-defined roles in the nervous system, particularly in the process of axon guidance, suggesting functional overlap and conservation in mechanism between that process and epithelial remodelling. We expand on the hypothesis that epithelial occluding junctions and synaptic junctions are compositionally equivalent and present a novel hypothesis that the mechanism of epithelial cell (re)integration and synaptic junction formation are shared. We highlight the importance of considering non-cadherin-based adhesion in our understanding of the mechanics of epithelial tissues and raise questions to direct future work. This article is part of the discussion meeting issue ‘Contemporary morphogenesis’.

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“…Convergent extension, which involves the exchange of cell boundaries, alters the aspect ratio of growing embryos (Sutherland et al, 2020). Intercalation of individual cells into a pre-existing epithelial layer has been described in epiboly and keel formation during zebrafish development, the developing murine ureteric bud, multiciliated cell development in Xenopus embryo, and in the extending branches of mammary organoids in 3D culture (Bruce and Heisenberg, 2020; Geldmacher-Voss et al, 2003; Neumann et al, 2018a; Packard et al, 2013; Stubbs et al, 2006; Wilson and Bergstralh, 2017). Moreover, re-integration of extruded cells has been observed in the Drosophila follicular epithelium (Bergstralh et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A Junction-Dependent Mechanism Drives Mammary Cell Intercalation for Ductal Elongation

Pfannenstein

Macara

2022

Preprint

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Mammary glands contain branched networks of ducts and alveoli that function to produce milk for offspring. While the murine luminal epithelium is organized as a cellular monolayer, it originates from multilayered structures called terminal end buds (TEB). The TEBs generate ducts of monolayered epithelial cells as they invade the fat pad but little is known about underlying mechanisms. While apoptosis provides a plausible mechanism for cavitation of the ductal lumen it does not account for elongation of ducts behind the TEBs. Our spatial calculations suggest that most cells in TEBs need to intercalate into the outermost luminal layer and that this migration of cells is the primary driver of cavitation and ductal elongation. To study the progression of multilayered to monolayered epithelium, we developed a quantitative cell culture assay that determines the efficiency of intercalation into an epithelial monolayer. Using this tool, we verified that loss of adherens junctions prevents stable integration of cells into monolayers, consistent with previous data in cultured cells and in primary tissue. Interestingly, tight junction (TJ) proteins also play a key role in this integration process. Although loss of the ZO1 TJ protein in intercalating cells suppresses intercalation, loss of ZO1 in the monolayer has the reverse effect, promoting intercalation even though ZO1 is not necessary for establishment of TJs. ZO1 positive puncta form between cells and the monolayer, which then resolves into a new intercellular boundary as intercalation proceeds. ZO1 loss also reduces engraftment when cells are transplanted into the mammary gland via intraductal injection. We further show that intercalation is dependent on dynamic cytoskeletal rearrangements in both the existing monolayer and intercalating cells. These data identify luminal cell rearrangements necessary for mammary gland development and suggest a molecular mechanism for integration of cells into an existing monolayer.

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Cell reintegration: Stray epithelial cells make their way home

Cited by 9 publications

References 49 publications

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Neuronal immunoglobulin superfamily cell adhesion molecules in epithelial morphogenesis: insights fromDrosophila

A Junction-Dependent Mechanism Drives Mammary Cell Intercalation for Ductal Elongation

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