aPKC is a key polarity molecule coordinating the function of three distinct cell polarities during collective migration

Wang, Heng; Qiu, Zhiqian; Xu, Zehao; Chen, Samuel John; Luo, Jun; Wang, Xiaobo; Chen, Jiong

doi:10.1242/dev.158444

Cited by 39 publications

(49 citation statements)

References 44 publications

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“…As the epithelial walls touched, aPKC was specifically reduced at the contact point ( Figure 2B Remodeling of polarized epithelium is regulated by endosome recycling, where aPKC and cadherins are removed from the cell surface by endocytosis and shuttled to other membrane domains (Ivanov et al, 2004;Wang et al, 2018). Immunostaining for endosomal protein Rab11 revealed abundant apical puncta where the epithelium fuses in both Xenopus and in mouse, coincident with loss of aPKC and Cdh1 relocalization ( Figure 2E-F).…”

Section: Rab11 and Endosome-mediated Epithelial Remodeling Are Requirmentioning

confidence: 99%

Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog/Gli Is Required for Tracheoesophageal Separation

Nasr

Mancini

Rankin

et al. 2019

Preprint

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Highlight bullet points:• The Sox2+ esophagus and Nkx2-1+ trachea arise from the separation of a single foregut tube through a series of cellular events conserved in mouse and Xenopus• Tracheoesophageal morphogenesis initiates with HH/Gli-dependent medial constriction of the gut tube mesenchyme at the Sox2-Nkx2-1 border • The foregut epithelial walls fuse forming a transient septum co-expressing Sox2 and Nkx2-1 • Downstream of HH/Gli Rab11-dependent endosome-mediated epithelial remodeling and localized extracellular matrix degradation separate the esophagus and trachea • HH/Gli mutations reveal the cellular basis of tracheoesophageal birth defects SUMMARY The trachea and esophagus arise from the separation of a common foregut tube during early fetal development. Mutations in key signaling pathways such as Hedgehog (HH)/Gli can disrupt tracheoesophageal (TE) morphogenesis and cause life-threatening birth defects (TEDs), however the underlying cellular mechanisms are unknown. Here we use mouse and Xenopus to define the HH/Gli-dependent processes orchestrating TE morphogenesis. We show that downstream of Gli the Foxf1+ splanchnic mesenchyme promotes medial constriction of the foregut at the boundary between the presumptive Sox2+ esophageal and Nkx2-1+ tracheal epithelium. We identify a unique boundary epithelium co-expressing Sox2 and Nkx2-1 that fuses to form a transient septum. Septum formation and resolution into distinct trachea and esophagus requires endosome-mediated epithelial remodeling involving the small GTPase Rab11, and localized extracellular matrix degradation. These are disrupted in Gli-deficient embryos. This work provides a new mechanistic framework for TE morphogenesis and informs the cellular basis of human TEDs.

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Section: Rab11 and Endosome-mediated Epithelial Remodeling Are Requirmentioning

confidence: 99%

Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog/Gli Is Required for Tracheoesophageal Separation

Nasr

Mancini

Rankin

et al. 2019

Preprint

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“…Our data also support a role for Pp1 in controlling F-actin stability, dynamics, and spatial organization. Similar to the pattern of activated Myo-II, cortical F-actin is normally high at the cluster periphery, although low levels are found between border cells 23, 25, 61 . Reduced Pp1 activity causes high levels of F-actin to redistribute from the cluster perimeter to surround entire cell cortices of individual border cells.…”

Section: Discussionmentioning

confidence: 66%

“…The rounder cell shapes suggested that Pp1 inhibition alters the cortical cytoskeleton of the border cells. Wild-type border cells exhibit a marked enrichment of F-actin at the cluster periphery, whereas lower levels are detected inside the cluster at contacts between border cells (Figure 6D,D’,F; Video 11) 25, 61 . Upon Pp1 inhibition, F-actin now accumulated around each individual border cell, especially at BC-BC membrane contacts, rather than just being enriched at outer cluster surfaces (Figure 6E,E’,G; Video 12).…”

Section: Resultsmentioning

confidence: 97%

Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration

Chen

Kotian

Aranjuez

et al. 2019

Preprint

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AbstractCollective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at internal cell-cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

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“…DE-Cad-GFP and DE-Cad-mCherry knock-in stocks were used as E-Cad reporters [49]. s lbo -GAL4, UAS-lifeact-GFP, UAS-LacZ stock was generously provided by Jiong Chen (Nanjing University) [92]. Fly stocks were raised on standard yeast-based media at 20°C, unless otherwise noted.…”

Section: Methodsmentioning

confidence: 99%

“…Ectopic actin patch number was quantified as described [92]. Actin patch present at the base of the leading edge protrusion was excluded from quantification since it is not ectopic.…”

Section: Methodsmentioning

confidence: 99%

Evolutionary rate covariation analysis of E-cadherin identifies Raskol as regulator of cell adhesion and actin dynamics inDrosophila

Raza

Choi

et al. 2018

Preprint

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The adherens junction couples the actin cytoskeletons of neighboring cells to provide the foundation for multicellular organization. The core of the adherens junction is the cadherin-catenin complex that arose early in the evolution of multicellularity to link cortical actin to intercellular adhesions. Over time, evolutionary pressures have shaped the signaling and mechanical functions of the adherens junction to meet specific developmental and physiological demands. Evolutionary rate covariation (ERC) identifies genes with correlated fluctuations in evolutionary rate that can reflect shared selective pressures and functions. Here we use ERC to identify genes with evolutionary histories similar to shotgun (shg), which encodes the Drosophila E-cadherin (DE-Cad) ortholog. Core adherens junction components α-catenin and p120-catenin displayed strong ERC correlations with shg, indicating that they evolved under similar selective pressures during evolution between Drosophila species. Further analysis of the shg ERC profile revealed a collection of genes not previously associated with shg function or cadherin-mediated adhesion. We then analyzed the function of a subset of ERC-identified candidate genes by RNAi during border cell (BC) migration and identified novel genes that function to regulate DE-Cad. Among these, we found that the gene CG42684, which encodes a putative GTPase activating protein (GAP), regulates BC migration and adhesion. We named CG42684 raskol (“to split” in Russian) and show that it regulates DE-Cad levels and actin protrusions in BCs. We propose that Raskol functions with DE-Cad to restrict Ras/Rho signaling and help guide BC migration. Our results demonstrate that a coordinated selective pressure has shaped the adherens junction and this can be leveraged to identify novel components of the complexes and signaling pathways that regulate cadherin-mediated adhesion.Author SummaryThe establishment of intercellular adhesions facilitated the genesis of multicellular organisms. The adherens junction, which links the actin cytoskeletons of neighboring cells, arose early in the evolution of multicellularity and selective pressures have shaped its function and molecular composition over time. In this study, we used evolutionary rate covariation (ERC) analysis to examine the evolutionary history of the adherens junction and to identify genes that coevolved with the adherens junction gene shotgun, which encodes the Drosophila E-cadherin (DE-Cad). ERC analysis of shotgun revealed a collection of genes with similar evolutionary histories. We then tested the role of these genes in border cell migration in the fly egg chamber, a process that requires the coordinated regulation of cell-cell adhesion and cell motility. Among these, we found that a previously uncharacterized gene CG42684, which encodes a putative GTPase activating protein (GAP), regulates the collective cell migration of border cells, stabilizes cell-cell adhesions and regulates the actin dynamics. Our results demonstrate that components of the adherens junction share an evolutionary history and that ERC analysis is a powerful method to identify novel components of cell adhesion complexes in Drosophila.

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aPKC is a key polarity molecule coordinating the function of three distinct cell polarities during collective migration

Cited by 39 publications

References 44 publications

Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog/Gli Is Required for Tracheoesophageal Separation

Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog/Gli Is Required for Tracheoesophageal Separation

Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration

Evolutionary rate covariation analysis of E-cadherin identifies Raskol as regulator of cell adhesion and actin dynamics inDrosophila

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