Telophase correction refines division orientation in stratified epithelia

Lough, Kendall J.; Byrd, Kevin M.; Descovich, Carlos Patiño; Spitzer, Danielle C; Beaudoin, Gerard M.J.; Reichardt, Louis F.; Williams, Scott

doi:10.1101/668244

Cited by 8 publications

(12 citation statements)

References 74 publications

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“…Reoriented division and delamination amongst basal cells both contribute to populating the suprabasal compartment. However, recent intravital imaging reveals that dynamic factors pertaining to adhesion and geometry actively ensure proper execution of these processes (Box et al, 2019;Lough et al, 2019;Mesa et al, 2018;Miroshnikova et al, 2017). Though the present study did not aim to compare delamination with asymmetric division, we posit that preferential adhesions established by Dia1 expression gradients would act in both cases to channel proliferative output into basal layer packing (Fig.…”

Section: Discussionmentioning

confidence: 82%

Dia1 Coordinates Differentiation and Cell Sorting in a Stratified Epithelium

Harmon

Devany

Gardel

2021

Preprint

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Although implicated in adhesion, few studies address how actin assembly factors guide cell positioning in multicellular tissue. The formin, Dia1, localizes to the proliferative basal layer of epidermis. In organotypic cultures, Dia1 depletion reduced basal cell density and resulted in stratified tissue with disorganized differentiation and proliferative markers. Since crowding induces differentiation in epidermal tissue, we hypothesized that Dia1 allows cells to reach densities amenable to differentiation prior to stratification. Consistent with this hypothesis, forced crowding of Dia1-deficient cells rescued transcriptional abnormalities. Dia1 promotes rapid growth of lateral adhesions, a behavior consistent with the ability of cells to remain monolayered when crowded. In aggregation assays, cells sorted into distinct layers based on Dia1 expression status. These results suggested that as basal cells proliferate, reintegration and packing of Dia1-positive daughter cells is favored while Dia1-negative cells tend to delaminate to a suprabasal compartment. These data demonstrate how formin expression patterns play a crucial role in constructing distinct domains within stratified epithelia.SummaryHarmon et al demonstrate that differential expression of an actin nucleator, the formin, Dia1, drives cell sorting and maintains distinct morphological domains within an epithelial tissue. This illuminates the possible utility of evolving a large formin family in orchestrating the compartmentalization and differentiation of complex tissues.

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Section: Discussionmentioning

confidence: 82%

Dia1 Coordinates Differentiation and Cell Sorting in a Stratified Epithelium

Harmon

Devany

Gardel

2021

Preprint

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“…We used LUGGIGE to generate two tissue-specific Afdn loss-offunction models ( Fig. 1A): (1) knockdown with a previously validated Afdn 2711 shRNA (Lough et al, 2019); (2) knockout using RFP-tagged Cre recombinase injected into Afdn fl/fl mice (Beaudoin et al, 2012). For the first strategy, we injected E9.5 CD1 mice with lentivirus harboring the Afdn 2711 shRNA and an mRFP1 fluorescent reporter fused to histone-2B (H2B-mRFP1) ( Fig.…”

Section: Results and Discussion Afadin Is Required For Secondary Palamentioning

confidence: 99%

“…These sequences were selected from The RNAi Consortium (TRC) Mission shRNA library (Sigma) versions 1.0, 1.5 and 2.0, and cloned using complementary annealed oligonucleotides with AgeI/EcoRI linkers. For Afdn, we used an shRNA that had been previously validated with our lentiviral injection technique (Lough et al, 2019). shRNA clones are identified by the gene name with the nucleotide base (NCBI Accession number) where the 21-nucleotide target sequence begins in superscript (e.g.…”

Section: Constructs and Rnaimentioning

confidence: 99%

Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1

Lough

Spitzer

et al. 2020

Development

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Cleft palate (CP), one of the most common congenital conditions, arises from failures in secondary palatogenesis during embryonic development. Several human genetic syndromes featuring CP and ectodermal dysplasia have been linked to mutations in genes regulating cell-cell adhesion, yet mouse models have largely failed to recapitulate these findings. Here, we use in utero lentiviral-mediated genetic approaches in mice to provide the first direct evidence that the nectin-afadin axis is essential for proper palate shelf elevation and fusion. Using this technique, we demonstrate that palatal epithelial conditional loss of afadin (Afdn)an obligate nectin-and actin-binding proteininduces a high penetrance of CP, not observed when Afdn is targeted later using Krt14-Cre. We implicate Nectin1 and Nectin4 as being crucially involved, as loss of either induces a low penetrance of mild palate closure defects, while loss of both causes severe CP with a frequency similar to Afdn loss. Finally, expression of the human disease mutant NECTIN1 W185X causes CP with greater penetrance than Nectin1 loss, suggesting this alteration may drive CP via a dominant interfering mechanism.

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“…Further, in the skin epidermis LGN participates in a tension-dependent correction mechanism of spindle orientation. During telophase, LGN collaborates with AJ tension sensitive proteins, such as a-catenin and afadin, to perpendicularly orient spindles (Lough et al, 2019). This mechanism suggests an extra layer of control over spindle orientation, where the spindle machinery itself cooperates with mechanoresponsive cortical elements to position the spindle.…”

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confidence: 99%

“…Interestingly, in this context Pins/Mud are necessary for the apico-basal positioning of the spindle (left) but not for its planar positioning (right) . (C) In mammals, deletion of the spindle regulator LGN differentially affects mitotic spindle orientation, perhaps based on its apical vs. lateral localization in different epithelia (Byrd et al, 2016;Lough et al, 2019). In the mouse skin epidermis, LGN loss elicits mostly planar cell divisions, and in the oral tongue epithelium, it randomizes the spindle orientation.…”

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confidence: 99%

Orchestration of tissue‐scale mechanics and fate decisions by polarity signalling

Gomes

Iden

2021

The EMBO Journal

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Eukaryotic development relies on dynamic cell shape changes and segregation of fate determinants to achieve coordinated compartmentalization at larger scale. Studies in invertebrates have identified polarity programmes essential for morphogenesis; however, less is known about their contribution to adult tissue maintenance. While polarity-dependent fate decisions in mammals utilize molecular machineries similar to invertebrates, the hierarchies and effectors can differ widely. Recent studies in epithelial systems disclosed an intriguing interplay of polarity proteins, adhesion molecules and mechanochemical pathways in tissue organization. Based on major advances in biophysics, genome editing, highresolution imaging and mathematical modelling, the cell polarity field has evolved to a remarkably multidisciplinary ground. Here, we review emerging concepts how polarity and cell fate are coupled, with emphasis on tissue-scale mechanisms, mechanobiology and mammalian models. Recent findings on the role of polarity signalling for tissue mechanics, micro-environmental functions and fate choices in health and disease will be summarized.

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Telophase correction refines division orientation in stratified epithelia

Cited by 8 publications

References 74 publications

Dia1 Coordinates Differentiation and Cell Sorting in a Stratified Epithelium

Dia1 Coordinates Differentiation and Cell Sorting in a Stratified Epithelium

Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1

Orchestration of tissue‐scale mechanics and fate decisions by polarity signalling

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