Cadherin Subclasses: Differential Expression and Their Roles in Neural Morphogenesis
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Abstract:
Cells are able to adhere selectively to particular cell types. This property of cells is considered to play an important role in development of the nervous system. For example, the selective adhesiveness might be essential for developing neurons to seek and bind to the particular target cells, or it might work for sorting different types of neurons and glias to establish the highly ordered stereotypic cell arrangement in neural tissues during development. In fact, it is known that disaggregated neural cells can reconstitute the original tissue-like structures when reaggregated by allocating themselves in a tissue-specific pattern (Fujisawa 1971). It is likely that such cell behaviors are regulated at least partly by the molecules involved in cell-cell adhesion, although many other factors, such as cell-matrix adhesion molecules, cell migration activators or inhibitors, chemotactic factors, and growth factors, might also be involved (Dodd and Jessel 1988).Keywords:
Expression (computer science)
Tissue morphogenesis during development is dependent on activities of the cadherin family of cell–cell adhesion proteins that includes classical cadherins, protocadherins, and atypical cadherins (Fat, Dachsous, and Flamingo). The extracellular domain of cadherins contains characteristic repeats that regulate homophilic and heterophilic interactions during adhesion and cell sorting. Although cadherins may have originated to facilitate mechanical cell–cell adhesion, they have evolved to function in many other aspects of morphogenesis. These additional roles rely on cadherin interactions with a wide range of binding partners that modify their expression and adhesion activity by local regulation of the actin cytoskeleton and diverse signaling pathways. Here we examine how different members of the cadherin family act in different developmental contexts, and discuss the mechanisms involved.
Cell Sorting
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Classic cadherins can be grouped based on their deduced primary structures. Among them the type I cadherins have been well characterized; however, little is known about non-type I cadherins. In this study we characterized two human type II cadherins, cadherin-6 and cadherin-14, using a cDNA transfection system. They were each detected as two bands electrophoretically, were expressed on the external cell surface at cell-cell contact sites, and were associated with caten- ins. Direct sequencing of the N-terminal amino acids showed that the two bands of cadherin-14 corresponded to precursor and mature forms, whereas the two bands of cadherin-6 both had the N-terminal sequence of the mature form. Unlike type I cadherins, both cadherin-6 and -14 were not protected from trypsin degradation by Ca2+. We evaluated their adhesive functions by a long term cell aggregation method. The results suggest that both cadherin-6 and -14 have cell-cell binding strengths virtually equivalent to that of E-cadherin and that their binding specificities are distinct from that of E-cadherin. Cadherin-6 and -14 interacted with each other in an incomplete manner. They have a QAI tripeptide in the first extracellular subdomain instead of the HAV motif that is characteristic of type I cadherins and is intimately involved in the adhesive function. The QAI tripeptide, however, appeared not to be involved in the adhesive functions of cadherin-6 and -14.
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Cadherins, Ca(2+)-dependent cell adhesion molecules, are known to play essential roles in morphogenesis and organogenesis. However, the role of cadherins in liver organogenesis remains poorly understood. The aim of this study is to clarify the expression patterns and levels of these cadherins in the developing and maturing mouse liver.The expression of E- and N-cadherin was investigated immunohistochemically and levels were determined by immunoblots.In the hepatic primordia E-cadherin, but not N- cadherin, was weakly expressed. As development proceeded, N-cadherin became coexpressed with E-cadherin in a single hepatocyte. The expression was uniform throughout the liver and the amount of these cadherins gradually increased. In the first postnatal week during the initial formation of the architecture of the liver lobule, the distribution of these cadherins gradually changed to the complementary pattern of the adult type, i.e. E-cadherin was expressed in the periportal zones, while N-cadherin was expressed in the perivenous zones.The complementary expression patterns of E- and N-cadherin between the periportal and perivenous zones developed gradually after birth. This specific regional localization of each cadherin may serve as an aid in defining different functional regions in the mouse liver lobule.
Primordium
Organogenesis
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In many carcinomas, E-cadherin is considered to be a prognostic marker for patient survivals, and its decreased expression is associated with metastatic disease. Among renal cell carcinomas (RCCs), however, only 20% of tumors express E-cadherin, whereas a much higher percentage express other cadherins, e.g., N-cadherin and cadherin-6 (T. Shimazui et al, Cancer Res., 56: 3234-3237, 1996). Among these cadherins expressed in RCCs, cadherin-6 has been identified as a major cadherin in the renal proximal tubules and in the tumors themselves. Hence, we have investigated the relationship between prognosis and cadherin-6 expression in tumor cells in 43 patients with RCC. Expression of cadherin-6, E-cadherin, and alpha-catenin was detected immunohistochemically and evaluated microscopically as normal, heterogeneous, or absent. Normal, heterogeneous, and absent expression of cadherin-6 were observed in 19, 16, and 8 of 43 cases, respectively. Coexpression of E-cadherin and cadherin-6 was detected in only 10 cases. Among 30 tumors in which E-cadherin expression was absent, 24 expressed cadherin-6. In addition, the expression pattern of alpha-catenin correlated more highly with that of cadherin-6 than it did with E-cadherin (P = 0.0003 versus 0.025). In survival analyses, aberrant expression of cadherin-6 correlated with poor survivals both among all patients (P = 0.0009) and in those with E-cadherin-absent RCC (P = 0.0008). These results suggest that cadherin-6 is a major cadherin playing an essential role in cell-cell adhesion in E-cadherin-absent RCC.
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AbstractBy immunological methods, we show that the monoclonal antibody 6D5 which reacts specifically with Xenopus laevis XB/U-cadherin, also binds to mouse P-cadherin and to chicken B-cadherin but not to the respective E-cadherins (L-CAM) or other "classical" cadherins in these species. In the first extracellular domain, three amino acid residues are identified that are shared by frog XB/U-cadherin, chicken B-cadherin and mammalian P-cadherins but not by the other "classical" cadherins. With few exceptions, the other cadherins possess residues at these positions that are also characteristic of each type of cadherin. Moreover, the expression patterns of P-, B-, and XB/U-cadherin in mouse, chicken and frog are more similar to each other than they are to those of the E-cadherins, L-CAM or other classical cadherins. Taken together, our results suggest that mammalian P-cadherins, chicken B-cadherin and frog XB/U-cadherin are closely related, if not homologous, molecules. A number of differences in the expression patterns between P-, B-, and XB/U-cadherin indicate that these molecules assume differential morphogenetic roles in different species.Key Words: cell-cell adhesioncalcium-dependentcadherin superfamilyexpression analysiscross-species homologuesphylogenesis
VE-cadherin
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The factors governing the pattern formation process in the early morphogenesis of a marine colonial hydroid, Dynamena pumila, have been studied. Two different types of morphogenesis have been distinguished. Morphogenesis of the first type goes on via changes in cell shape and cell axis orientation, while morphogenesis of the second type is based upon the active coordinated cell movements associated with cell rearrangements. It was shown that morphogenesis of both types can be considered as cascades in which any event is a consequence of the previous one. The spatial structure of each developmental stage contains information about the direction and the initial conditions of further morphogenesis. So, an "epigenetic program" of morphogenesis gradually originates in the course of development and provides the stable reproduction of spatial structures. It is reasonable to consider the activity of epigenetic factors guiding Dynamena morphogenesis (geometry/topology of an embryo, heterogeneity of an embryo spatial structure, configuration of the field of mechanical stresses of the embryo surface) as "morphomechanical programming" of morphogenesis.
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Objective To explore the expression of E-cadherin and N-cadherin in HCC and the relationship between E-cadherin and N-cadherin,and to seek their correlations to metastasis in HCC. Methods Expression of E-cadherin and N-cadherin was detected in 46 cases of HCC and 10 cases of normal liver specimens by immunohistochemical EnVision.Results In 46 cases of HCC,34 cases(73.9%) and 30 cases(65.2%) showed low expression of E-cadherin and N-cadherin,respectively,whereas all of the 10 cases(100%) showed high expression of the both.The expression of E-casherin and N-cadherin was related with the malignant degree and metastasis potential(P0.05), and showed positive correlation between each other(r=0.579,P0.01). Conclusions The expression levels of E-cadherin and N-cadherin in HCC are lower than normal liver specimen.N-cadherin positively correlates with E-cadherin.The lower expression of E-cadherin and N-cadherin suggests poorly differentiated and higher potential of metasbasis.
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The entire coding sequences for five possible human cadherins, named cadherin-4,-8,-11,-12 and-13, were determined. The deduced amino acid sequences of cadherin-4 and cadherin-13 showed high homology with those of chicken R-cadherin or chicken T-caciherin, suggesting that cadherin-4 and cadherin-13 are mammalian homologues of the chicken R-cadherin or T-cadherin. Comparison of the extracellular domain of these proteins with those of other cadherins and cadherin-related proteins clarifies characteristic structural features of this domain. The domain is subdivided into five subdomains, each of which contains a cadherin-specific motif characterized by well-conserved amino acid residues and short amino acid sequences. Moreover, each subdomain has unique features of its own. The comparison also provides additional evidence for two structurally different types of cadherins: the first type includes B-, E-, EP-, M, N-, P-and R-cadherins and cadherin-4; the second type includes cadherin-5 through cadherin-12. Cadherin-13 lacks the sequence corresponding to the cytoplasmic domain of typical cadherins, but the extracellular domain shares most of the features common to the extracellular domain of cadherins, especially those of the first type of cadherins, suggesting that cadherin-13 is a special type of cadherin. These results, and those of other recent cloning studies, indicate that many cadherins with different properties are expressed in various tissues of different organisms.
Homology
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