Adherens Junctions Revisualized: Organizing Cadherins as Nanoassemblies

Yap, Alpha S.; Gómez, Guillermo A.; Parton, Robert G.

doi:10.1016/j.devcel.2015.09.012

Cited by 110 publications

(104 citation statements)

References 120 publications

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“…In agreement with electron microscopy, high magnification confocal microscope analysis of N-cadherin staining revealed prominent disorganization of N-cadherin-containing AJCs in E14.5 Llgl1 cKO cortexes, even in the areas that maintained the integrity of the ventricular wall (Figure S4). Abnormal junctions may be the result from decreased levels of adherens junction proteins N-cadherin, α- and β-catenins, failure of cadherin-catenin protein complex formation, failure of cadherin-catenin complex delivery and retention at the plasma membrane, or failure of clustering and stabilization of adhesion complexes by association with the actin cytoskeleton (Yap et al, 2015). We found no differences in the total levels of cadherin and catenin proteins or in the cadherin-catenin complex formation in E14.5 Llgl1 cKO ENSCs (Figure 5E).…”

Section: Resultsmentioning

confidence: 99%

Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells

et al. 2017

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Malformations of cerebral cortex (MCC) are devastating developmental disorders. We report here that mice with embryonic neural stem cell-specific deletion of Llgl1 (Nestin-Cre/Llgl1fl/fl), a mammalian ortholog of Drosophila cell polarity gene lgl, exhibit MCC resembling severe periventricular heterotopia (PH). Immunohistochemical analyses and live cortical imaging of PH formation revealed that disruption of apical junctional complexes (AJCs) was responsible for PH in Nestin-Cre/Llgl1fl/fl brains. While it is well known that cell polarity proteins govern the formation of AJCs, the exact mechanisms remain unclear. We show that LLGL1 directly binds to and promotes internalization of N-cadherin, and N-cadherin/LLGL1 interaction is inhibited by aPKC-mediated phosphorylation of LLGL1, restricting the accumulation of AJCs to the basolateral-apical boundary. Disruption of N-cadherin-LLGL1 interaction during cortical development in vivo is sufficient for PH. These findings reveal a mechanism responsible for the physical and functional connection between cell polarity and cell-cell adhesion machineries in mammalian cells.

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Section: Resultsmentioning

confidence: 99%

Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells

et al. 2017

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“…In addition, clustering of the core proteins into puncta may be associated with the formation of stable interactions with the cytoskeleton. For example, the stability of E-cadherin clusters at adherens junctions is dependent on the actin cytoskeleton (reviewed in Yap et al., 2015), and cortical actin activity also regulates the mobility of GPI-linked proteins in nanoclusters (Goswami et al., 2008). …”

Section: Discussionmentioning

confidence: 99%

Robust Asymmetric Localization of Planar Polarity Proteins Is Associated with Organization into Signalosome-like Domains of Variable Stoichiometry

2016

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SummaryIn developing epithelia, the core planar polarity proteins physically interact with each other and localize asymmetrically at opposite cell ends, forming intercellular complexes that link the polarity of neighboring cells. Using quantitative imaging to examine the composition of the core protein complex in vivo, we find that complex composition is unexpectedly plastic. The transmembrane proteins Frizzled and Flamingo form a stoichiometric nucleus in the complex, while the relative levels of the other four core proteins can vary independently. Exploring the functional consequences of this, we show that robust cell polarization is achieved over a range of complex stoichiometries but is dependent on maintaining appropriate levels of the components Frizzled and Strabismus. We propose that the core proteins assemble into signalosome-like structures, where stable association is not dependent on one-to-one interactions with binding partners, and signaling functions can act over a wide range of complex compositions.

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“…Additional studies have shown that cadherin punctae formed by the clustering of E-cadherin along cell-cell boundaries can increase in size during the maturation of cell-cell junctions, and that they are important for cell-cell adhesion and force transmission in vivo (26,30). How E-cadherin molecules come together and form these punctae has been under intense investigation (31): Some studies have suggested that E-cadherin molecules are able to move along lateral membranes (32, 33), and one of the common themes emerging is the importance of the cortical actin cytoskeleton in their formation (26,31).Cdh2 (N-cadherin) adhesive junctions play an important role in mechanical coupling between cardiomyocytes (34, 35). Despite its potential importance, no detailed analysis has been carried out on the organization of Cdh2 during heart development.…”

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confidence: 99%

N-cadherin relocalization during cardiac trabeculation

Cherian

Fukuda

Augustine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During cardiac trabeculation, cardiomyocytes delaminate from the outermost (compact) layer to form complex muscular structures known as trabeculae. As these cardiomyocytes delaminate, the remodeling of adhesion junctions must be tightly coordinated so cells can extrude from the compact layer while remaining in tight contact with their neighbors. In this study, we examined the distribution of N-cadherin (Cdh2) during cardiac trabeculation in zebrafish. By analyzing the localization of a Cdh2-EGFP fusion protein expressed under the control of the zebrafish cdh2 promoter, we initially observed Cdh2-EGFP expression along the lateral sides of embryonic cardiomyocytes, in an evenly distributed pattern, and with the occasional appearance of punctae. Within a few hours, Cdh2-EGFP distribution on the lateral sides of cardiomyocytes evolves into a clear punctate pattern as Cdh2-EGFP molecules outside the punctae cluster to increase the size of these aggregates. In addition, Cdh2-EGFP molecules also appear on the basal side of cardiomyocytes that remain in the compact layer. Delaminating cardiomyocytes accumulate Cdh2-EGFP on the surface facing the basal side of compact layer cardiomyocytes, thereby allowing tight adhesion between these layers. Importantly, we find that blood flow/cardiac contractility is required for the transition from an even distribution of Cdh2-EGFP to the formation of punctae. Furthermore, using time-lapse imaging of beating hearts in conjunction with a Cdh2 tandem fluorescent protein timer transgenic line, we observed that Cdh2-EGFP molecules appear to move from the lateral to the basal side of cardiomyocytes along the cell membrane, and that Erb-b2 receptor tyrosine kinase 2 (Erbb2) function is required for this relocalization.T o maximize its function, the heart undergoes a series of morphological changes during development, with trabeculation being one of the main processes (1-5). Trabeculae initially appear as myocardial ridges in the outer curvature of the ventricle, and they are important for cardiac function, as evidenced by studies of hypo-and hypertrabeculation models (3,(6)(7)(8)(9)(10)(11). Previous studies have shown that Erbb2 signaling is essential for trabeculation (3,6,7,10,11). Moreover, disturbing blood flow or cardiac contractility in the ventricle perturbs trabeculation (4, 12, 13), suggesting an important role for mechanical forces in this process. Our understanding of the cellular mechanisms regulating trabeculation remains fairly limited. Cardiomyocytes in the early heart tube show an epithelium-like morphology (3,14). During trabeculation, some cardiomyocytes delaminate and enter the trabecular layer, where they join other trabecular cardiomyocytes to form ridge-like structures (3,15). Previous studies have shown that the most proximal cardiomyocytes in the trabecular layer remain tightly attached to the basal side of compact layer cardiomyocytes (3, 15). Some of the key molecules involved in cellcell adhesion belong to the cadherin family, and they also play crucial roles in...

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Adherens Junctions Revisualized: Organizing Cadherins as Nanoassemblies

Cited by 110 publications

References 120 publications

Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells

Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells

Robust Asymmetric Localization of Planar Polarity Proteins Is Associated with Organization into Signalosome-like Domains of Variable Stoichiometry

N-cadherin relocalization during cardiac trabeculation

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