Cadherins in early neural development.

During early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type" (Waddington in Nature 183: 1654-1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772-774, 1988; Lander in Cell 144: 955-969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

Revisiting Dscam diversity: lessons from clustered protocadherins.

The complexity of neuronal wiring relies on the extraordinary recognition diversity of cell surface molecules. Drosophila Dscam1 and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the striking diversity from a complex genomic locus, wherein the former encodes more than 10,000 distinct isoforms via alternative splicing, while the latter employs alternative promoters to attain isoform diversity. These structurally unrelated families show remarkably striking molecular parallels and even similar functions. Recent studies revealed a novel Dscam gene family with tandemly arrayed 5' cassettes in Chelicerata (e.g., the scorpion Mesobuthus martensii and the tick Ixodes scapularis), similar to vertebrate clustered Pcdhs. Likewise, octopus shows a more remarkable expansion of the Pcdh isoform repertoire than human. These discoveries of Dscam and Pcdh diversification reshape the evolutionary landscape of recognition molecule diversity and provide a greater understanding of convergent molecular strategies for isoform diversity. This article reviews new insights into the evolution, regulatory mechanisms, and functions of Dscam and Pcdh isoform diversity. In particular, the convergence of clustered Dscams and Pcdhs is highlighted.

Expresión de E-cadherina y células de Langerhans en verruga vulgar y papiloma bucal / Expression of E-cadherin and Langerhans cells in verruca vulgaris and oral papilloma

Introducción: la verruga vulgar y el papiloma bucal son lesiones provocadas por el virus papiloma humano se pueden encontrar presentes en la mayoría de las superfi cies cutáneas y mucosas, su comportamiento biológico es benigno. Las proteínas de adhesión como la E-cadherina, se encargan de mantener la organización y morfología celular, disminuyen su expresión epitelial en ciertas lesiones potencialmente cancerizables, y favorecen la migración e invasión celular ocasionando posiblesmetástasis. Las células de Langerhans, son células presentadoras deantígeno que activan el sistema inmunológico para proteger al organismocontra patógenos o sustancias extrañas. Objetivo: Determinar el grado de expresión de E-cadherina y de células de Langerhans en verruga vulgar y papiloma bucal. Material y métodos: Se realizó un estudio descriptivo y retrospectivo, en el cual se incluyeron 16 bloques con tejido incluido en parafi na con diagnóstico de verruga vulgar, ycuatro diagnosticados como papiloma bucal, todos los casos fueron corroborados con la tinción de hematoxilina y eosina. La determinacióndel grado de expresión de las células de Langerhans y E-cadherina se realizó por medio de la técnica de inmunohistoquímica, la valoraciónse llevó a cabo de manera semicuantitativa, y se realizó estadísticadescriptiva. Resultados: La expresión de E-cadherina en verruga vulgar fue intensa tanto en cantidad como intensidad, mientras que en papiloma bucal fue moderada también en ambos casos; las células de Langerhans mostraron una inmunotinción moderada en las lesiones de verruga vulgar en intensidad y cantidad; en el caso de papiloma bucal esta inmunotinción en intensidad y cantidad fue leve. . Conclusiones:Los resultados mostraron que las proteínas de adhesión E-cadherinano pierden su expresión en la verruga vulgar y papiloma bucal, lo cualconfi rma su benignidad...

Introduction: verruca vulgaris and oral papilloma are lesions causedby the human papillomavirus. They can be found on most skin and mucosalsurfaces, and their biological behavior is benign. Adhesion proteinssuch as E-cadherins are responsible for maintaining cell morphologyand organization; they decrease the expression in certain potentiallycancerous epithelial lesions and promote cell migration and invasion,causing possible metastasis. Langerhans cells are antigen-presentingcells that activate the immune system to protect the body againstpathogens or foreign substances. Objective: To determine the degreeof expression of E-cadherin and Langerhans cells in verruca vulgarisand oral papilloma. Material and methods: We performed a descriptiveand retrospective study involving 16 paraffi n-embedded tissue blocksof diagnosed cases of verruca vulgaris and 4 paraffi n-embedded tissueblocks identifi ed as oral papilloma. The diagnosis was previouslyconfi rmed by hematoxylin and eosin staining. The degree of expressionof Langerhans cells and E-Cadherin was determined by immunohistochemistry,while the evaluation was carried out semiquantitatively,with descriptive statistics being performed. Results: The expression ofE-cadherin in verruca vulgaris was strong in terms of both quantityand intensity, whereas in the case of oral papilloma it was moderatefor both. Langerhans cells showed moderate immunostaining for bothintensity and quantity in verruca vulgaris-type lesions, while for oralpapilloma, the immunostaining was also mild in both cases. Conclusions:The results suggest that the expression of E-cadherin adhesionproteins does not diminish in verruca vulgaris and oral papilloma,which confi rms their benignity...

Aberrant expression and functions of protocadherins in human malignant tumors.

Protocadherins (PCDHs) are a group of transmembrane proteins belonging to the cadherin superfamily and are subdivided into "clustered" and "non-clustered" groups. PCDHs vary in both structure and interaction partners and thus regulate multiple biological responses in complex and versatile patterns. Previous researches showed that PCDHs regulated the development of brain and were involved in some neuronal diseases. Recently, studies have revealed aberrant expression of PCDHs in various human malignant tumors. The down-regulation or absence of PCDHs in malignant cells has been associated with cancer progression. Further researches suggest that PCDHs may play major functions as tumor suppressor by inhibiting the proliferation and metastasis of cancer cells. In this review, we focus on the altered expression of PCDHs and their roles in the development of cancer progression. We also discuss the potential mechanisms, by which PCDHs are aberrantly expressed, and its implications in regulating cancers.

Protocadherins branch out: Multiple roles in dendrite development.

The proper formation of dendritic arbors is a critical step in neural circuit formation, and as such defects in arborization are associated with a variety of neurodevelopmental disorders. Among the best gene candidates are those encoding cell adhesion molecules, including members of the diverse cadherin superfamily characterized by distinctive, repeated adhesive domains in their extracellular regions. Protocadherins (Pcdhs) make up the largest group within this superfamily, encompassing over 80 genes, including the ∼60 genes of the α-, ß-, and γ-Pcdh gene clusters and the non-clustered δ-Pcdh genes. An additional group includes the atypical cadherin genes encoding the giant Fat and Dachsous proteins and the 7-transmembrane cadherins. In this review we highlight the many roles that Pcdhs and atypical cadherins have been demonstrated to play in dendritogenesis, dendrite arborization, and dendritic spine regulation. Together, the published studies we discuss implicate these members of the cadherin superfamily as key regulators of dendrite development and function, and as potential therapeutic targets for future interventions in neurodevelopmental disorders.

A cadherin-like protein influences Bacillus thuringiensis Cry1Ab toxicity in the oriental armyworm, Mythimna separata.

Cadherins comprise a family of calcium-dependent cell adhesion proteins that act in cell-cell interactions. Cadherin-like proteins (CADs) in midguts of some insects act as receptors that bind some of the toxins produced by the Bacillus thuringiensis (Bt). We cloned a CAD gene associated with larval midguts prepared from Mythimna separata. The full-length cDNA (MsCAD1, GenBank Accession No. JF951432) is 5642 bp, with an open reading frame encoding a 1757 amino acid and characteristics typical of insect CADs. Expression of MsCAD1 is predominantly in midgut tissue, with highest expression in the 3rd- to 6th-instars and lowest in newly hatched larvae. Knocking-down MsCAD1 decreased Cry1Ab susceptibility, indicated by reduced developmental time, increased larval weight and reduced larval mortality. We expressed MsCAD1 in E. coli and recovered the recombinant protein, rMsCAD1, which binds Cry1Ab toxin. Truncation analysis and binding experiments revealed that a contiguous 209-aa, located in CR11 and CR12, is the minimal Cry1Ab binding region. These results demonstrate that MsCAD1 is associated with Cry1Ab toxicity and is one of the Cry1Ab receptors in this insect. The significance of this work lies in identifying MsCAD1 as a Cry1Ab receptor, which helps understand the mechanism of Cry1Ab toxicity and of potential resistance to Bt in M. separata.

Atypical cadherins Celsr1-3 and planar cell polarity in vertebrates.

Cadherin EGF LAG seven-pass G-type receptors 1, 2, and 3 (Celsr1-3) form a family of three atypical cadherins with multiple functions in epithelia and in the nervous system. During the past decade, evidence has accumulated for important and distinct roles of Celsr1-3 in planar cell polarity (PCP) during the development of the brain and some other organs. Although Celsr function in PCP is conserved from flies to mammals, other functions may be more distantly related, with Celsr working only with one or a subset of the classical core PCP partners. Here, we review the literature on Celsr, focusing on PCP and particularly on brain development.

Biochemical and biophysical origins of cadherin selectivity and adhesion strength.

Classical cadherins are single-pass transmembrane proteins mediating adhesive interactions between animal cells. As such, they play key roles during morphogenetic movements, in cell sorting and in tissue integrity. Being positioned at the cell-cell interface, cadherins are most likely important players in mechanotransduction pathways. This review briefly outlines our current understanding of the biochemical and biophysical basis for various adhesive properties of cadherins and the ensuing intercellular adhesive strength and specificity. We summarize the attempts to explain cadherin specificity from their ultrastructural features and their adhesive behavior at the single molecule level. The role of cadherin clusters and cooperative binding is then reviewed. Lastly, we consider the attempts to understand the link between local stress and the adhesive properties of cadherin-mediated junctions.

Cadherin complexity: recent insights into cadherin superfamily function in C. elegans.

Cadherin superfamily proteins mediate cell-cell adhesion during development. The C. elegans embryo is a powerful system for analyzing how cadherins function in highly stereotyped morphogenetic events. In the embryo, the classical cadherin HMR-1 acts along with the Rac pathway and SAX-7/L1CAM during gastrulation. As adherens junctions mature, PAR complex proteins differentially regulate cadherin complex localization, and SRGP-1/Slit/Robo GAP aids adhesion by promoting membrane bending. Once adherens junctions form, actin is linked to the cell surface via HMP-1/α-catenin, whose actin binding activity is regulated in novel ways. FMI-1/Flamingo and CDH-4/Fat-like regulate axonal morphology of both pioneer and follower neurons. C. elegans thus continues to be useful for uncovering precise functions for cadherin superfamily proteins and their associates in a simple metazoan.

Bacterial cadherin domains as carbohydrate binding modules: determination of affinity constants to insoluble complex polysaccharides.

Cadherin (CA) and cadherin-like (CADG) doublet domains from the complex polysaccharide-degrading marine bacterium, Saccharophagus degradans 2-40, demonstrated reversible calcium-dependent binding to different complex polysaccharides, which serve as growth substrates for the bacterium. Here we describe a procedure based on adsorption of CA and CADG doublet domains to different insoluble complex polysaccharides, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) for visualizing and quantifying the distribution of cadherins between the bound and unbound fractions. Scatchard plots were employed to determine the kinetics of interactions of CA and CADG with several complex carbohydrates. On the basis of these binding studies, the CA and CADG doublet domains are proposed to form a new family of carbohydrate-binding module (CBM).

The cadherin switch in ovarian high-grade serous carcinoma is associated with disease progression.

Ovarian high-grade serous carcinoma (HGSC) often has a poor prognosis because of late presentation, lack of sensitivity and specificity of screening modalities and the development of chemoresistance. New targeted therapy is required if survival in these cases is to improve. The profile of E-, P- and N-cadherins in ovarian cancer and its association with survival remain poorly understood. Reduced expression of E-cadherin in prostate cancer associated with increase in the expression of N- and P-cadherins is described as cadherin switch. We hypothesised that there is a switch in the expression of cadherins that regulates the behaviour of HGSC and possibly its outcome. To identify the stages of the cadherin switch in HGSC, we studied the immunoexpression of E-, P- and N-cadherins in a cohort of 177 cases of HGSC. High expression of P-cadherin was associated with poor patient survival and was significantly higher in stage 2 disease when compared with stage 1 and stage 3 disease (P = 0.033). In contrast, loss of E-cadherin was observed in stage 3 HGSC when compared with other stages (P = 0.050). E-, P- and N- cadherin expressions were significantly associated with disease outcome when assessed individually and in various combinations with an interesting profile. Our results indicate that the cadherin switch alters through progression of HGSC. The profile of combined cadherin expressions in association with survival raises expectations in targeted therapy.

'The missing genes: what happened to the heritability of psychiatric disorders?'.

Less than 2% of the 80-90% heritability of major psychiatric disease, for example, schizophrenia and manic-depressive illness is attributable to genes identified by linkage and association. Where is the missing heritability? The recently described PRDM9 gene imposes epigenetic stability on the XY body in male meiosis including Sapiens-specific variation relating to a gene pair (Protocadherin11XY) created by X to Y duplication at 6MYA. Thus sexually dimorphic variation that distinguishes the species may be transmitted between generations in epigenetic form that evades detection by linkage and association.

New insights into the evolution of metazoan cadherins.

Mining newly sequenced genomes of basal metazoan organisms reveals the evolutionary origin of modern protein families. Specific cell-cell adhesion and intracellular communication are key processes in multicellular animals, and members of the cadherin superfamily are essential players in these processes. Mammalian genomes contain over 100 genes belonging to this superfamily. By a combination of tBLASTn and profile hidden Markov model analyses, we made an exhaustive search for cadherins and compiled the cadherin repertoires in key organisms, including Branchiostoma floridae (amphioxus), the sea anemone Nematostella vectensis, and the placozoan Trichoplax adhaerens. Comparative analyses of multiple protein domains within known and novel cadherins enabled us to reconstruct the complex evolution in metazoa of this large superfamily. Five main cadherin branches are represented in the primitive metazoan Trichoplax: classical (CDH), flamingo (CELSR), dachsous (DCHS), FAT, and FAT-like. Classical cadherins, such as E-cadherin, arose from an Urmetazoan cadherin, which progressively lost N-terminal extracellular cadherin repeats, whereas its cytoplasmic domain, which binds the armadillo proteins p120ctn and ß-catenin, remained quite conserved from placozoa to man. The origin of protocadherins predates the Bilateria and is likely rooted in an ancestral FAT cadherin. Several but not all protostomians lost protocadherins. The emergence of chordates coincided with a great expansion of the protocadherin repertoire. The evolution of ancient metazoan cadherins points to their unique and crucial roles in multicellular animal life.

Cadherins in cerebellar development: translation of embryonic patterning into mature functional compartmentalization.

Cadherins are cell adhesion molecules with multiple morphogenic functions in brain development, for example, in neuroblast migration and aggregation, axon navigation, neural circuit formation, and synaptogenesis. More than 100 members of the cadherin superfamily are expressed in the developing and mature brain. Most of the cadherins investigated, in particular classic cadherins and δ-protocadherins, are expressed in the cerebellum. For several cadherin subtypes, expression begins at early embryonic stages and persists until mature stages of cerebellar development. At intermediate stages, distinct Purkinje cell clusters exhibit unique rostrocaudal and mediolateral expression profiles for each cadherin. In the chicken, mouse, and other species, the Purkinje cell clusters are separated by intervening raphes of migrating granule cells. This pattern of Purkinje cell clusters/raphes is, at least in part, continuous with the parasagittal striping pattern that is apparent in the mature cerebellar cortex, for example, for zebrin II/aldolase C. Moreover, subregions of the deep cerebellar nuclei, vestibular nuclei and the olivary complex also express cadherins differentially. Neuroanatomical evidence suggests that the nuclear subregions and cortical domains that express the same cadherin subtype are connected to each other, to form neural subcircuits of the cerebellar system. Cadherins thus provide a molecular code that specifies not only embryonic structures but also functional cerebellar compartmentalization. By following the implementation of this code, it can be revealed how mature functional architecture emerges from embryonic patterning during cerebellar development. Dysfunction of some cadherins is associated with psychiatric diseases and developmental impairments and may also affect cerebellar function.

Non-clustered protocadherin.

The cadherin family is classified into classical cadherins, desmosomal cadherins and protocadherins (PCDHs). Genomic structures distinguish between PCDHs and other cadherins, and between clustered and non-clustered PCDHs. The phylogenetic analysis with full sequences of non-clustered PCDHs enabled them to be further classified into three subgroups: δ1 (PCDH1, PCDH7, PCDH9, PCDH11 and PCDH20), δ2 (PCDH8, PCDH10, PCDH12, PCDH17, PCDH18 and PCDH19) and ε (PCDH15, PCDH16, PCDH21 and MUCDHL). ε-PCDH members except PCDH21 have either higher or lower numbers of cadherin repeats than those of other PCDHs. Non-clustered PCDHs are expressed predominantly in the nervous system and have spatiotemporally diverse expression patterns. Especially, the region-specific expressions of non-clustered PCDHs have been observed in cortical area of early postnatal stage and in caudate putaman and/or hippocampal formation of mature brains, suggesting that non-clustered PCDHs play roles in the circuit formation and maintenance. The non-clustered PCDHs appear to have homophilic/heterophilc cell-cell adhesion properties, and each member has diverse cell signaling partnership distinct from those of other members (PCDH7/TAF1; PCDH8/TAO2ß; PCDH10/Nap1; PCDH11/ß-catenin; PCDH18/mDab1). Furthermore, each PCDH has several isoforms with differential cytoplasmic sequences, suggesting that one PCDH isoform could activate intracellular signaling differential from other isoforms. These facts suggest that non-clustered PCDHs play roles as a mediator of a regulator of other molecules as well as cell-cell adhesion. Furthermore, some non-clustered PCDHs have been considered to be involved in neuronal diseases such as autism-spectrum disorders, schizophrenia, and female-limited epilepsy and cognitive impairment, suggesting that they play multiple, tightly regulated roles in normal brain function. In addition, some non-clustered PCDHs have been suggested as candidate tumor suppressor genes in several tissues. Although molecular adhesive and regulatory properties of some PCDHs began to be unveiled, the endeavor to understand the molecular mechanism of non-clustered PCDH is still in its infancy and requires future study.

N-cadherin is depleted from proximal tubules in experimental and human acute kidney injury.

Ischemia remains the most common cause of acute kidney injury (AKI). Decreased intercellular adhesion and alterations in adhesion molecules may contribute to the loss of renal function observed in AKI. In the present study, we evaluated the distribution of adhesion molecules in the human kidney and analyzed their expression in human and experimental AKI. Specimens of human kidneys obtained from patients with and without AKI were stained for the cell adhesion molecules E-cadherin, N-cadherin and beta-catenin. Experimental AKI in rats was induced by renal artery clamping. Immunostaining and immunoblotting were carried out for E-cadherin, N-cadherin and beta-catenin. Proximal tubule cells from opossum kidneys (OKs) were used to analyze the effect of chemical hypoxia (ATP depletion) in vitro. In the adult human kidney, N-cadherin was expressed in proximal tubules, while E-cadherin was expressed in other nephron segments. beta-Catenin was expressed in both proximal and distal tubules. In human AKI and in ischemic rat kidneys, N-cadherin immunostaining was depleted from proximal tubules. There was no change in E-cadherin or beta-catenin. In vitro, OK cells expressed N-cadherin only in the presence of collagen, and ATP depletion led to a depletion of N-cadherin. Collagen IV staining was reduced in ischemic rat kidneys compared to controls. The results of the study suggest that N-cadherin may play a significant role in human and experimental AKI.

7TM-Cadherins: developmental roles and future challenges.

The 7TM-Cadherins, Celsr/Flamingo/Starry night, represent a unique subgroup of adhesion-GPCRs containing atypical cadherin repeats, capable of homophilic interaction, linked to the archetypal adhesion-GPCR seven-transmembrane domain. Studies in Drosophila provided a first glimpse of their functional properties, most notably in the regulation of planar cell polarity (PCP) and in the formation of neural architecture. Many of the developmental functions identified in flies are conserved in vertebrates with PCP predicted to influence the development of multiple organ systems. Details of the molecular and cellular functions of 7TM-Cadherins are slowly emerging but many questions remain unanswered. Here the developmental roles of 7TM-Cadherins are discussed and future challenges in understanding their molecular and cellular roles are explored.

Expression of protocadherin-19 in the nervous system of the embryonic zebrafish.

We have analyzed the expression pattern of protocadherin-19, a member of the delta2-protocadherins, in the nervous system of developing zebrafish using in situ hybridization methods. mRNA encoding protocadherin-19 (Pcdh19) began to be expressed at about 12 hours post fertilization (hpf) showing a segmental expression pattern in the anterior 1/3 of the neural keel, with strong expression in the presumptive forebrain, cerebellum/rhombomere 1 and rhombomere 4. Pcdh19 expression in the posterior neural keel was continuous and confined to the midline region. By 24 hpf, Pcdh19 was expressed widely in the brain and spinal cord, with higher expression levels in the ventral telencephalon, dorsal and central thalamus, optic tectum, central tegmentum, cerebellum and dorsolateral regions of the hindbrain. As development proceeded, Pcdh19 expression domains became restricted to the dorsal and/or lateral regions of the central nervous system, and Pcdh19 expression was not detected in the spinal cord of two- and three-day old embryos. Pcdh19 was also expressed by the eye primordium, developing retina, lens and otic vesicle. Similar to its expression in the brain, Pcdh19 expression in the eye and ear was also spatially and temporally regulated.

Expression of cadherin superfamily genes in brain vascular development.

Cadherins are Ca2+-dependent cell adhesion molecules that are important in vertebrate nervous system development. We identified seven members of the cadherin superfamily (cadherin-4, cadherin-5, cadherin-6, cadherin-6, cadherin-11, protocadherin-1, and protocadherin-17) and an intracellular binding partner of delta-protocadherins, protein phosphatase 1alpha, as novel markers for developing blood vessels in the ferret brain. Some of the cadherin molecules are restricted to specific brain regions or a subset of blood vessels. The expression levels show a peak during perinatal vascular development. Our results suggest that multiple cadherins, which are also involved in neurogenesis, are regulators of angiogenesis in developing vertebrate brain.

Sequence and structural determinants of strand swapping in cadherin domains: do all cadherins bind through the same adhesive interface?

Cadherins are cell surface adhesion proteins important for tissue development and integrity. Type I and type II, or classical, cadherins form adhesive dimers via an interface formed through the exchange, or "swapping", of the N-terminal beta-strands from their membrane-distal EC1 domains. Here, we ask which sequence and structural features in EC1 domains are responsible for beta-strand swapping and whether members of other cadherin families form similar strand-swapped binding interfaces. We created a comprehensive database of multiple alignments of each type of cadherin domain. We used the known three-dimensional structures of classical cadherins to identify conserved positions in multiple sequence alignments that appear to be crucial determinants of the cadherin domain structure. We identified features that are unique to EC1 domains. On the basis of our analysis, we conclude that all cadherin domains have very similar overall folds but, with the exception of classical and desmosomal cadherin EC1 domains, most of them do not appear to bind through a strand-swapping mechanism. Thus, non-classical cadherins that function in adhesion are likely to use different protein-protein interaction interfaces. Our results have implications for the evolution of molecular mechanisms of cadherin-mediated adhesion in vertebrates.