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Leptospirosis, caused by pathogenic species of Leptospira, is the most widespread zoonosis and has emerged as a major public health problem worldwide. The adhesion of pathogenic Leptospira to host cells, and to extracellular matrix (ECM) components, is likely to be necessary for the ability of leptospires to penetrate, disseminate and persist in mammalian host tissues. Previous work demonstrated that pathogenic L. interrogans binds to host cells more efficiently than to ECM. Using two independent screening methods, mass spectrometry and protein arrays, members of the cadherin family were identified as potential L. interrogans receptors on mammalian host surfaces. We focused our investigation on vascular endothelial (VE)-cadherin, which is widely expressed on endothelia and is primarily responsible for endothelial cell-cell adhesion. Monolayers of EA.hy926 and HMEC-1 endothelial cells produce VE-cadherin, bind L. interrogans in vitro, and are disrupted upon incubation with the bacteria, which may reflect the endothelial damage seen in vivo. Dose-dependent and saturable binding of L. interrogans to the purified VE-cadherin receptor was demonstrated and pretreatment of purified receptor or endothelial cells with function-blocking antibody against VE-cadherin significantly inhibited bacterial attachment. The contribution of VE-cadherin to leptospiral adherence to host endothelial cell surfaces is biologically significant because VE-cadherin plays an important role in maintaining the barrier properties of the vasculature. Attachment of L. interrogans to the vasculature via VE-cadherin may result in vascular damage, facilitating the escape of the pathogen from the bloodstream into different tissues during disseminated infection, and may contribute to the hemorrhagic manifestations of leptospirosis. This work is first to describe a mammalian cell surface protein as a receptor for L. interrogans.
Hearing and balance rely on the transduction of mechanical stimuli arising from sound waves or head movements into electrochemical signals. This archetypal mechanoelectrical transduction process occurs in the hair-cell stereocilia of the inner ear, which experience continuous oscillations driven by undulations in the endolymph in which they are immersed. The filamentous structures called tip links, formed by an intertwined thread composed of an heterotypic complex of cadherin 23 and protocadherin 15 ectodomain dimers, connect each stereocilium to the tip of the lower sterocilium, and must maintain their integrity against continuous stimulatory deflections. By using single molecule force spectroscopy, here we demonstrate that in contrast to the case of classical cadherins, tip-link cadherins are mechanoresilient structures even at the exceptionally low Ca2+ concentration of the endolymph. We also show that the D101G deafness point mutation in cadherin 23, which affects a Ca2+ coordination site, exhibits an altered mechanical phenotype at the physiological Ca2+ concentration. Our results show a remarkable case of functional adaptation of a protein's nanomechanics to extremely low Ca2+ concentrations and pave the way to a full understanding of the mechanotransduction mechanism mediated by auditory cadherins.
Classic cadherins, which are adhesion molecules in cell-cell adherens junctions, have a large contribution to the construction of the animal body. Their molecular structures show clear differences between chordate and nonchordate metazoans. Although nonchordate classic cadherins have cadherin superfamily-specific extracellular repeats (CRs) and a highly conserved cytoplasmic domain (CP), these cadherins have a unique extracellular domain that is absent from vertebrate and ascidian classic cadherins. We called this the primitive classic cadherin domain (PCCD). To understand the roles of the PCCD, we constructed and characterized a series of mutant forms of the Drosophila classic cadherin DE-cadherin. Biochemical analyses indicated that the last two CRs and PCCD form a special structure with proteolytic cleavage. Mutations in the PCCD did not eliminate the cell-cell-binding function of DE-cadherin in cultured cells, but prevented the cadherin from efficiently translocating to the plasma membrane in epithelial cells of the developing embryo. In addition, genetic rescue assays suggested that although CP-mediated control plays a central role in tracheal fusion, the role of the PCCD in efficient recruitment of DE-cadherin to apical areas of the plasma membranes is also important for dynamic epithelial morphogenesis. We propose that there is a fundamental difference in the mode of classic cadherin-mediated cell-cell adhesion between chordate and nonchordate metazoans.
Classical cadherins form parallel cis-dimers that emanate from a single cell surface. It is thought that the cis-dimeric form is active in cell-cell adhesion, whereas cadherin monomers are likely to be inactive. Currently, cis-dimers have been shown to exist only between cadherins of the same type. Here, we show the specific formation of cis-heterodimers between N- and R-cadherins. E-cadherin cannot participate in these complexes. Cells coexpressing N- and R-cadherins show homophilic adhesion in which these proteins coassociate at cell-cell interfaces. We performed site- directed mutagenesis studies, the results of which support the strand dimer model for cis-dimerization. Furthermore, we show that when N- and R-cadherins are coexpressed in neurons in vitro, the two cadherins colocalize at certain neural synapses, implying biological relevance for these complexes. The present study provides a novel paradigm for cadherin interaction whereby selective cis-heterodimer formation may generate new functional units to mediate cell-cell adhesion.
The desmosomal cadherins (DCs), desmocollin (Dsc) and desmoglein (Dsg), are the adhesion molecules of desmosomes, intercellular adhesive junctions of epithelia and cardiac muscle. Both the DCs and desmosomes have demonstrably essential roles in mammalian development. In order to initiate their study in a more tractable developmental system we have characterised zebrafish DCs and examined their roles in early zebrafish development.
Classical cadherins are a metazoan-specific family of homophilic cell-cell adhesion molecules that regulate morphogenesis. Type I and type IV cadherins in this family function at adherens junctions in the major epithelial tissues of vertebrates and insects, respectively, but they have distinct, relatively simple domain organizations that are thought to have evolved by independent reductive changes from an ancestral type III cadherin, which is larger than derived paralogs and has a complicated domain organization. Although both type III and type IV cadherins have been identified in hexapods and branchiopods, the process by which the type IV cadherin evolved is still largely unclear.
Drugs of abuse alter synaptic connections in the reward circuitry of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation in the ventral tegmental area and is recruited to the synaptic membranes of excitatory synapses onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.
The desmosomal cadherins, desmogleins (Dsgs) and desmocollins (Dscs), comprise the adhesive core of intercellular junctions known as desmosomes. Although these adhesion molecules are known to be critical for tissue integrity, mechanisms that coordinate their trafficking into intercellular junctions to regulate their proper ratio and distribution are unknown. We demonstrate that Dsg2 and Dsc2 both exhibit microtubule-dependent transport in epithelial cells but use distinct motors to traffic to the plasma membrane. Functional interference with kinesin-1 blocked Dsg2 transport, resulting in the assembly of Dsg2-deficient junctions with minimal impact on distribution of Dsc2 or desmosomal plaque components. In contrast, inhibiting kinesin-2 prevented Dsc2 movement and decreased its plasma membrane accumulation without affecting Dsg2 trafficking. Either kinesin-1 or -2 deficiency weakened intercellular adhesion, despite the maintenance of adherens junctions and other desmosome components at the plasma membrane. Differential regulation of desmosomal cadherin transport could provide a mechanism to tailor adhesion strength during tissue morphogenesis and remodeling.
Stat3 (Signal Transducer and Activator of Transcription-3) is activated by a number of receptor and nonreceptor tyrosine kinases. We recently demonstrated that engagement of E-cadherin, a calcium-dependent, cell to cell adhesion molecule which is often required for cells to remain tightly associated within the epithelium, also activates Stat3. We now examined the effect of two other classical cadherins, cadherin-11 and N-cadherin, whose expression often correlates with the epithelial to mesenchymal transition occurring in metastasis of carcinoma cells, upon Stat3 phosphorylation and activity. Our results indicate that engagement of these two cadherins also, can trigger a dramatic surge in Stat3 activity. This activation occurs through upregulation of members of the IL6 family of cytokines, and it is necessary for cell survival, proliferation and migration. Interestingly, our results also demonstrate for the first time that, in sharp contrast to Stat3, the activity of Erk (Extracellular Signal Regulated kinase) was unaffected by cadherin-11 engagement. Further examination indicated that, although IL6 was able to activate Erk in sparsely growing cells, IL6 could not induce an increase in Erk activity levels in densely growing cultures. Most importantly, cadherin-11 knock-down did allow Erk activation by IL6 at high densities, indicating that it is indeed cadherin engagement that prevents Erk activation by IL6. The fact that the three classical cadherins tested so far, E-cadherin, N-cadherin and cadherin11, which are present in essentially all tissues, actually activate Stat3 regardless of their role in metastasis, argues for Stat3 as a central survival, rather than invasion factor.
The cell-cell adhesion molecule N-cadherin, with its associated catenins, is expressed by differentiating skeletal muscle and its precursors. Although N-cadherin's role in later events of skeletal myogenesis such as adhesion during myoblast fusion is well established, less is known about its role in earlier events such as commitment and differentiation. Using an in vitro model system, we have determined that N-cadherin- mediated adhesion enhances skeletal muscle differentiation in three-dimensional cell aggregates. We transfected the cadherin-negative BHK fibroblastlike cell line with N-cadherin. Expression of exogenous N-cadherin upregulated endogenous beta-catenin and induced strong cell-cell adhesion. When BHK cells were cultured as three-dimensional aggregates, N-cadherin enhanced withdrawal from the cell cycle and stimulated differentiation into skeletal muscle as measured by increased expression of sarcomeric myosin and the 12/101 antigen. In contrast, N-cadherin did not stimulate differentiation of BHK cells in monolayer cultures. The effect of N-cadherin was not unique since E-cadherin also increased the level of sarcomeric myosin in BHK aggregates. However, a nonfunctional mutant N-cadherin that increased the level of beta-catenin failed to promote skeletal muscle differentiation suggesting an adhesion-competent cadherin is required. Our results suggest that cadherin-mediated cell-cell interactions during embryogenesis can dramatically influence skeletal myogenesis.
Autophagy is a lysosomal degradation pathway that plays an essential role in neuronal homeostasis and is perturbed in many neurological diseases. Transcriptional downregulation of fat was previously observed in a Drosophila model of the polyglutamine disease Dentatorubral-pallidoluysian atrophy (DRPLA) and this was shown to be partially responsible for autophagy defects and neurodegeneration. However, it is still unclear whether a downregulation of mammalian Fat orthologues is associated with neurodegeneration in mice. We hereby show that all four Fat orthologues are transcriptionally downregulated in the cerebellum in a mouse model of DRPLA. To elucidate the possible roles of single Fat genes, this study concentrates on Fat3. This fat homologue is shown to be the most widely expressed in the brain. Conditional knockout (KO) of Fat3 in brains of adult mice was attempted using the inducible Thy1Cre(ERT2) SLICK H line. Behavioral and biochemical analysis revealed that mice with conditional KO of Fat3 in the brain display no abnormalities. This may be ascribed either to the limited efficiency of the KO strategy pursued or to the lack of effect of Fat3 KO on autophagy.
Fat, Fat-like, and Dachsous family cadherins are giant proteins that regulate planar cell polarity (PCP) and cell adhesion in bilaterians. Their evolutionary origin can be traced back to prebilaterian species, but their ancestral function(s) are unknown. We identified Fat-like and Dachsous cadherins in Hydra, a member of phylum Cnidaria a sister group of bilaterian. We found Hydra does not possess a true Fat homolog, but has homologs of Fat-like (HyFatl) and Dachsous (HyDs) that localize at the apical membrane of ectodermal epithelial cells and are planar polarized perpendicular to the oral-aboral axis of the animal. Using a knockdown approach we found that HyFatl is involved in local cell alignment and cell-cell adhesion, and that reduction of HyFatl leads to defects in tissue organization in the body column. Overexpression and knockdown experiments indicate that the intracellular domain (ICD) of HyFatl affects actin organization through proline-rich repeats. Thus, planar polarization of Fat-like and Dachsous cadherins has ancient, prebilaterian origins, and Fat-like cadherins have ancient roles in cell adhesion, spindle orientation, and tissue organization.
Classical cadherins, a set of ~20 related recognition and signaling molecules, have been implicated in many aspects of neural development, including the formation and remodeling of synapses. Mechanisms underlying some of these steps have been studied by expressing N-cadherin (cdh2), a Type 1 cadherin, in heterologous cells, but analysis is complicated because widely used lines express cdh2 endogenously. We used CRISPR-mediated gene editing to generate a Human embryonic kidney (HEK)293 variant lacking Cdh2, then compared the behavior of rodent cortical and hippocampal neurons co-cultured with parental, cdh2 mutant and cdh2-rescued 293 lines. The comparison demonstrated that Cdh2 promotes neurite branching and that it is required for three synaptic organizers, neurologin1 (NLGL1), leucine-rich repeat transmembrane protein 2 (LRRtm2), and Cell Adhesion Molecule 1 (Cadm1/SynCAM) to stimulate presynaptic differentiation, assayed by clustering of synaptic vesicles at sites of neurite-293 cell contact. Similarly, Cdh2 is required for a presynaptic organizing molecule, Neurexin1β, to promote postsynaptic differentiation in dendrites. We also show that another Type I cadherin, Cdh4, and a Type II cadherin, Cdh6, can substitute for Cdh2 in these assays. Finally, we provide evidence that the effects of cadherins require homophilic interactions between neurites and the heterologous cells. Together, these results indicate that classical cadherins act together with synaptic organizers to promote synaptic differentiation, perhaps in part by strengthening the intracellular adhesion required for the organizers to act efficiently. We propose that cadherins promote high affinity contacts between appropriate partners, which then enable synaptic differentiation.
Control of cell polarity is crucial during tissue morphogenesis and renewal, and depends on spatial cues provided by the extracellular environment. Using micropatterned substrates to impose reproducible cell-cell interactions, we show that in the absence of other polarizing cues, cell-cell contacts are the main regulator of nucleus and centrosome positioning, and intracellular polarized organization. In a variety of cell types, including astrocytes, epithelial cells, and endothelial cells, calcium-dependent cadherin-mediated cell-cell interactions induce nucleus and centrosome off-centering toward cell-cell contacts, and promote orientation of the nucleus-centrosome axis toward free cell edges. Nucleus and centrosome off-centering is controlled by N-cadherin through the regulation of cell interactions with the extracellular matrix, whereas the orientation of the nucleus-centrosome axis is determined by the geometry of N-cadherin-mediated contacts. Our results demonstrate that in addition to the specific function of E-cadherin in regulating baso-apical epithelial polarity, classical cadherins control cell polarization in otherwise nonpolarized cells.
Since, similarly to humans, songbirds learn their vocalization through imitation during their juvenile stage, they have often been used as model animals to study the mechanisms of human verbal learning. Numerous anatomical and physiological studies have suggested that songbirds have a neural network called 'song system' specialized for vocal learning and production in their brain. However, it still remains unknown what molecular mechanisms regulate their vocal development. It has been suggested that type-II cadherins are involved in synapse formation and function. Previously, we found that type-II cadherin expressions are switched in the robust nucleus of arcopallium from cadherin-7-positive to cadherin-6B-positive during the phase from sensory to sensorimotor learning stage in a songbird, the Bengalese finch. Furthermore, in vitro analysis using cultured rat hippocampal neurons revealed that cadherin-6B enhanced and cadherin-7 suppressed the frequency of miniature excitatory postsynaptic currents via regulating dendritic spine morphology.
Cadherin linkages between adjacent stereocilia and microvilli are essential for mechanotransduction and maintaining their organization. They are anchored to actin through interaction of their cytoplasmic domains with related tripartite complexes consisting of a class VII myosin and adaptor proteins: Myo7a/SANS/Harmonin in stereocilia and Myo7b/ANKS4B/Harmonin in microvilli. Here, we determine high-resolution structures of Myo7a and Myo7b C-terminal MyTH4-FERM domain (MF2) and unveil how they recognize harmonin using a novel binding mode. Systematic definition of interactions between domains of the tripartite complex elucidates how the complex assembles and prevents possible self-association of harmonin-a. Several Myo7a deafness mutants that map to the surface of MF2 disrupt harmonin binding, revealing the molecular basis for how they impact the formation of the tripartite complex and disrupt mechanotransduction. Our results also suggest how switching between different harmonin isoforms can regulate the formation of networks with Myo7a motors and coordinate force sensing in stereocilia.
Desmosomes are large, macromolecular protein assemblies that mechanically couple the intermediate filament cytoskeleton to sites of cadherin-mediated cell adhesion, thereby providing structural integrity to tissues that routinely experience large forces. Proper desmosomal adhesion is necessary for the normal development and maintenance of vertebrate tissues, such as epithelia and cardiac muscle, while dysfunction can lead to severe disease of the heart and skin. Therefore, it is important to understand the relationship between desmosomal adhesion and the architecture of the molecules that form the adhesive interface, the desmosomal cadherins (DCs). However, desmosomes are embedded in two plasma membranes and are linked to the cytoskeletal networks of two cells, imposing extreme difficulty on traditional structural studies of DC architecture, which have yielded conflicting results. Consequently, the relationship between DC architecture and adhesive function remains unclear. To overcome these challenges, we utilized excitation-resolved fluorescence polarization microscopy to quantify the orientational order of the extracellular and intracellular domains of three DC isoforms: desmoglein 2, desmocollin 2, and desmoglein 3. We found that DC ectodomains were significantly more ordered than their cytoplasmic counterparts, indicating a drastic difference in DC architecture between opposing sides of the plasma membrane. This difference was conserved among all DCs tested, suggesting that it may be an important feature of desmosomal architecture. Moreover, our findings suggest that the organization of DC ectodomains is predominantly the result of extracellular adhesive interactions. We employed azimuthal orientation mapping to show that DC ectodomains are arranged with rotational symmetry about the membrane normal. Finally, we performed a series of mathematical simulations to test the feasibility of a recently proposed antiparallel arrangement of DC ectodomains, finding that it is supported by our experimental data. Importantly, the strategies employed here have the potential to elucidate molecular mechanisms for diseases that result from defective desmosome architecture.
There is a growing body of evidence to implicate reversible tyrosine phosphorylation as an important mechanism in the control of the adhesive function of cadherins. We previously demonstrated that the receptor protein tyrosine phosphatase PTPmu associates with the cadherin-catenin complex in various tissues and cells and, therefore, may be a component of such a regulatory mechanism (Brady-Kalnay, S. M., D.L. Rimm, and N.K. Tonks. 1995. J. Cell Biol. 130:977- 986). In this study, we present further characterization of this interaction using a variety of systems. We observed that PTPmu interacted with N-cadherin, E-cadherin, and cadherin-4 (also called R-cadherin) in extracts of rat lung. We observed a direct interaction between PTPmu and E-cadherin after coexpression in Sf9 cells. In WC5 cells, which express a temperature-sensitive mutant form of v-Src, the complex between PTPmu and E-cadherin was dynamic, and conditions that resulted in tyrosine phosphorylation of E-cadherin were associated with dissociation of PTPmu from the complex. Furthermore, we have demonstrated that the COOH-terminal 38 residues of the cytoplasmic segment of E-cadherin was required for association with PTPmu in WC5 cells. Zondag et al. (Zondag, G., W. Moolenaar, and M. Gebbink. 1996. J. Cell Biol. 134: 1513-1517) have asserted that the association we observed between PTPmu and the cadherin-catenin complex in immunoprecipitates of the phosphatase arises from nonspecific cross-reactivity between BK2, our antibody to PTPmu, and cadherins. In this study we have confirmed our initial observation and demonstrated the presence of cadherin in immunoprecipitates of PTPmu obtained with three antibodies that recognize distinct epitopes in the phosphatase. In addition, we have demonstrated directly that the anti-PTPmu antibody BK2 that we used initially did not cross-react with cadherin. Our data reinforce the observation of an interaction between PTPmu and E-cadherin in vitro and in vivo, further emphasizing the potential importance of reversible tyrosine phosphorylation in regulating cadherin function.
p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal. Mutation of this motif resulted in a cadherin variant that was both p120 uncoupled and resistant to endocytosis. In endothelial cells, in which dynamic changes in adhesion are important components of angiogenesis and inflammation, a vascular endothelial cadherin (VE-cadherin) mutant defective in endocytosis assembled normally into cell-cell junctions but potently suppressed cell migration in response to vascular endothelial growth factor. These results reveal the mechanistic basis by which p120 stabilizes cadherins and demonstrate that VE-cadherin endocytosis is crucial for endothelial cell migration in response to an angiogenic growth factor.
In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.
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