Morphogenetic roles of classic cadherinsbiology.hunter.cuny.edu/cellbio/Feinstein Cell Bio 2013... · 2009-04-03 · Invertebrate classic cadherins A classic cadherin-type molecule,

Morphogenetic roles of classic cadherins Masatoshi Takeichi

Kyoto University, Kyoto, Japan

Classic cadherins, which are known to be crucial for homotypic cell-cell adhesion, have been found to be present not only in vertebrate but also in invertebrate species. Their three-dimensional structures, novel functions, and novel expression patterns were reported recently. These have been important steps towards a deeper understanding of the morphogenetic roles of this family

of molecules.

Current Opinion in Cell Biology 1995, 7:619-627

Introduction

Animal morphogenesis involves dynamic arrangement and rearrangement of cells and cell layers. Classic cadherins, which are homophilic Ca2+-dependent cell-cell adhesion molecules, are considered to be regulators of such processes. These molecules, which include E-, N- and P-cadherin, represent a subfamily of the cadherin superfamily [1], and their pivotal roles in cell-cell adhesion have been established. Other members of the superfamily differ in domain structure from the classic cadherins [1-3], and one of them was even identified as a peptide transporter [4°]. Thus, the biological functions of this superfamily may be diverse. In this article, I review recent progress in our understanding of the morphogenetic roles of the classic cadherin subfamily, as most important information on this subject has been accumulated only for this subfamily. Cytoplasmic events associated with the cadherin function are not focused upon particularly in this review.

Type I versus type II classic cadherins

The classic cadherin subfamily is defined by their highly conserved cytoplasmic domain, which associates with catenins: ct-catenin, ~-catenin, plakoglobin, and p120 [5°,6°]. More than 15 members have been identified for this subfamily. They can, however, be subgrouped into types I and II on the basis of small but significant variations in amino acid sequence [7,8]. Although the activity of the type ! group in cell adhesion is well established, this is not the case for many o f the type II molecules, cDNAs encoding some o f the type II molecules have been transfected into L cells, and their adhesion activity then assayed. As far as published results are concerned, the transfected cells showed a typical cadherin-mediated aggregation [9°,10°°], suggesting that the type II cadherins are functionally similar to the type I group, at least in the L-cell transfection system. To seek functional differences, if present, between the two

groups, one would need to employ other assay systems. As described below, some of the type II molecules are expressed in loosely associated cells. These molecules, therefore, could be responsible for weaker intercellular adhesion as compared to the type I molecules.

Invertebrate classic cadherins

A classic cadherin-type molecule, DE-cadherin, was cloned for the first time from an invertebrate, using Drosophila [11"°]; its existence had been expected because of the presence of ct-catenin and [3-catenin (Armadillo) in invertebrate species [12,13] and from other observations [14]. DE-cadherin differs somewhat from the vertebrate classic cadherins. Its extracellular domain is much longer than that of the vertebrate molecules due to the presence o f additional repeats and the insertion of a cysteine-rich sequence as well as of a sequence with similarity to the laminin-A globular domain or neurexin at its proximal portion. The cytoplasmic domain is, on the other hand, considerably conserved between DE-cadherin and vertebrate classic cadherins. Consistently, DE-cadherin associates with /~ -ca ten in and Armadillo, and confers Ca2+-dependent aggregating ability on cells, as do the vertebrate classic cadhefins. The unique sequences in the extracellular domain may, however, endow DE-cadherin with unknown additional functions.

DE-cadherin is expressed mostly in epithelial tissues at the apical region of cell-cell contacts. These distributions are reminiscent of those o f vertebrate E-cadherin or L-CAM, suggesting that they are functionally homologous. Mesodermal and neural tissues do not express DE-cadherin (with some exceptions) but instead express other cadherins (Y Iwai, S Hirano, T Usui, M Takeichi, T Uemura, unpublished data). Thus, multiple cadherins are expressed in a tissue-specific or region-specific manner in Drosophila, as is the case in the vertebrates. These findings suggest that

© Current Biology Ltd ISSN 0955-0674 619

620 Cell-to-cell contact and extracellular matrix

cadherin-mediated morphogenetic mechanisms are at least in part conserved between the invertebrates and vertebrates.

The three-dimensional structure of the

amino-terminal domains of E- and N-cadherin

The extracellular domain of the vertebrate classic cadherins can be divided into five repeated subdomains on the basis of amino acid sequence, often referred to as ECl-5. These subdomains differ from the ‘cadherin repeats’ defined previously [15]: there are four repeats that are shifted a little towards the carboxyl terminus relative to ECl-5. The three-dimensional structures of E- and N-cadherin at the amino-terminal region were determined by nuclear magnetic resonance spectroscopy [ 16*.] and X-ray crystallography [ 17**], respectively. The results of these studies suggest that the ECl-5 subdivisions roughly correspond to the actual subdomain units of these proteins. Moreover, the X-ray analysis suggests that the N-cadherin extracellular domain forms a dimer, designated as the ‘strand dime?, in which two monomers are arranged in parallel at the plasma membrane. Each unit of the dimer interacts with that of another strand dimer on the opposite membrane,

forming an ‘adhesion dimer’ at their amino terminus. As a whole, it was proposed that the dimers are arranged like a zipper at the intercellular space (Fig. 1). However, an early quick-freeze, deep-etch study of cell-cell junctions did not reveal such a pattern of protein arrangement; instead, the cadherin-like molecules were observed as rod-like structures, each independently bridging the plasma membranes [18]. The alternative model, therefore, would be that the strand and adhesion dimers are arranged to form a rod- or cylinder-like oligomer rather than a linear zipper.

Amino acid residues flanking the HAV motif (single- letter code for amino acids), which was previously identified as a recognition site between cadherin molecules, are localized to the adhesion dimer interface, consistent with this proposed role. The above and another analyses [19] also suggest that Ca2+, an ion essential for cadherin function, is involved in linking the five successive subdomains to confer a rod-shape morphology on cadherin molecules (Fig. 1). This model accords with electron microscopic observations [20*]. There are, however, some inconsistencies between those observations; for example, the electron microscopic and nuclear magnetic resonance studies did not reveal the presence of cadherin dimers. Dimer formation may, therefore, require special conditions. Despite such discrepancies, the folding patterns of the molecules

(b)

0 1995 Current Opinion in Cell Biology

Fig. 1. Models of cadherin structure and interactions. (a) A three-dimensional model of the structure of the extracellu- jar domain of classic cadherins. The HAV motif thought to be involved in cadherin interactions and the Ca*+-binding sites are shown. (b) The zipper model for cadherin interaction, showing homophilic interactions between cadherin molecules expressed on the plasma membranes (m) of adjacent cells. Note that two types of dimer formation are involved. N, amino terminus.

Morphogenetic roles of classic cadherins Takeichi 621

reported are largely consistent with the biological properties of cadherins. These models, therefore, no doubt facilitate our further understanding of the structure and function of this molecular family.

rablc 1. Interactions between classic cadherin subtypes.

Type ’ Type II

Cadherin Organism E P N R L 6 68 7 11

E MOlW + - - - f +

P MOUWZ + - - - -

N Mouse/chicken + * - - - - -

R Mouse/chicken + - -

L’ Chicken + +

B Chicken +

66 Chicken + f

7 Chicken +

11 Mouse +

Results from different laboratories [9*,10**,21,221 are summarized. -, not

cross-reactive; f, partially cross-reactive; +, cross-reactive. Open spaces, data

not available. ‘-’ does not necessarily mean that they are completely not

cross-reactive; weak interactions may occur. l L, L-CAM.

Specificities in homophilic cadherin interactions

In principle, classic cadherins interact homophilically with each other, preferentially binding to like molecules. This was found not only for type I classic cadherins but also for members of the type II group. On the basis of this property of cadherins, two cell populations expressing different cadherins form separate aggregates when mixed. Exceptional cases have been observed, however, and thus the interactions between two given cadherins should be classified into the following three types (Table 1): those in which little or no heterophilic interaction occurs; those in which weak heterophilic interaction occurs; and those in which homophilic and heterophilic interactions are indistinguishable. In the second group, cells with one cadherin can adhere to those with another cadherin by forming chimeric aggregates, but they segregate from one another within the aggregates [10”,21]. The third type is mostly represented by interspecies homologues. As for combinations from a single species, B-cadherin and L-CAM, both Ii-om the chicken, exhibit this type of interaction [22]. The expression patterns of these two cadherins greatly overlap each other, suggesting that

they are functionally redundant. In addition, it should be noted that a single cell type, in general, expresses multiple cadherin subtypes, and their combination varies with the cell type. Combinatory action of multiple cadherins is, therefore, likely to be important in the determination of adhesive specificity of cells in vivo.

The molecular basis of the specificity in cadherin interactions still remains to be elucidated. The results of the three-dimensional analysis of N-cadherin discussed above suggest that multiple portions of the amino- terminal domain, including the HAV-flanking region, are involved in the adhesive interactions between the molecules. Even small changes in their sequences could alter the specificity. Incidentally, it should be noted that the I-WV motif is not conserved in type II cadherins. HAV cannot, therefore, be cadherin interactions, but sequence could rather be specificity.

a key sequence for general the variations within this used for the alteration of

Heterotypic interactions of cadherins with other

molecules

Cadherins have long been believed to be ‘homophilic’ adhesion molecules; however, an exception was discovered in a lymphocyte adhesion system. A subpopulation of T lymphocytes is known to associate with mucosal epithelia. These T cells express the integrin orEp7 in the human [23**] and crM29Op7 in the mouse [24**], but not E-cadherin. However, the attachment of these lymphocytes to epithelial cells is inhibited by antibodies to E-cadherin expressed by the latter. Together with other results, evidence was presented that E-cadherin interacts with aEfi7/aM290p7 [23”,24**]. The finding of the heterophilic binding of E-cadherin to an integrin raised an intriguing possibility that similar types of heterophilic cadherin interactions may occur in other systems. If this is the case, cadherins are involved in an even more complex adhesion network than ever before thought. It has also been reported that certain populations of fetal thymocytes express E-cadherin [25].

The possibility of another type of heterophilic cadherin interaction was reported recently [26’]. The fibroblast growth factor receptor-l contains a short sequence with homology to the HAV region of N-cadherin [26*]. Peptides containing this sequence can specifically inhibit neurite outgrowth stimulated by N-cadherin. It was therefore suggested that N-cadherin interacts with this receptor at the HAV region and generates a signal to promote neurite outgrowth. This model is intriguing, as it proposes that the cadherin extracellular domain has a kind of ligand activity for receptors. Biochemical evidence for this hypothetical interaction, however, remains to be provided.


Effects on morphogenesis of suppression of cadherin function or its overexpression

To obtain evidence for morphogenetic roles of cadherins, in viva experiments are crucial. As an approach to this end, the E-cadherin gene was knocked out in mice [27*,28*]. The E-cadherin-deficient mouse embryos cannot normally develop into blastocysts; this genetic study confirmed the importance of E-cadherin in the organization of pre-implantation embryos, which was previously suggested by the use of blocking antibodies. The N-cadherin gene has also been mutated (GL Radice, M Takeichi, RO Hynes, unpublished data): in mice without functional N-cadherin, the myocardium was disorganized, resulting in the blockage of heart development, and the neural tube and somites were also malformed. Injection of antisense oligonucleotides of cadherin into Xenopus embryos also caused dissociation of their blastomeres [29].

Dominant-negative constructs of cadherins can also suppress their activity. Two kinds of dominant-negative construct have been used. One encodes proteins in which the extracellular domain has a large deletion but the cytoplasmic domain is intact (AE), and the other generates proteins in which the cytoplasmic domain is deleted but the extracellular domain remains intact (AC). Whereas the effect of BE is already established, it is interesting to note that the AC construct can also cause partial cell dissociation when injected into Xenopus embryos [30*]. It probably does so by competing with the endogenous cadherins in their homophilic interactions. Consistent with this idea, the action of AC was cadherin-type specific. However, AC-type constructs did not significantly affect cell adhesion when transfected into cell lines [31]. The Xenopus system, therefore, must be exceptionally sensitive to these constructs. When AE constructs of Xenopus XB-cadherin and N-cadherin were injected into dorsal blastomeres of 32-cell stage Xenopus embryos, tissues descending from these cells were disorganized [32*]. One interesting observation in this experiment was that XB-cadherin was more efficient than N-cadherin in inducing the tissue perturbation.

Use of dominant-negative cadherins disclosed other interesting aspects of cadherin function in development. When a BE-type construct was expressed in the mesoderm, muscle differentiation was prohibited [33*]. As muscle differentiation requires cell-cell interactions, cadherins may be a key component of this process. More recently, a similar construct was expressed in mouse intestinal epithelial cells by a transgenic method [34*]. In these epithelial cells, not only cell-cell contacts but also cell-matrix adhesion were disrupted. Moreover, these cells precociously entered into a death program. These findings suggest that cadherin-mediated adhesion affects multiple processes in epithelial development. Results from another type of experiment, exogenous expression of intact cadherin molecules in cell lines,

indicate that cadherins can affect cell phenotypes as well as growth. Introducing E-cadherin into cells of a retinal pigment cell line, which endogenously express other cadherin subtypes, caused alterations in their polarity, and even induced the assembly of desmosomes, which had originally been absent [35**]. Transfection of an a-catenin-deficient cell line with its cDNA, which was effective in cadherin reactivation, resulted in a retardation of cell growth [36*]. A role of cadherins in cell differentiation was also suggested by use of blocking antibodies [37].

Depletion of B-catenin would also be expected to induce cadherin dysfunction, and such was the case in a carcinoma line in which this catenin is truncated [38*,39*]. Also, injection of antisense oligonucleotides of fi-catenin into Xenopus eggs caused abnormal development: the embryos had defects in dorsal structures [40**]. However, the overexpression of intact cadherins in embryos resulted in a similar phenotype. These paradoxical results were interpreted by assuming the presence of a p-catenin-associated signaling pathway involved in dorsal differentiation; this pathway, but not cadherin function, might have been blocked by not only the oligonucleotide injection but also cadherin overexpression. On the other hand, the overexpression of intact p-catenin in Xenopus embryos caused a duplication of the embryonic axis [41**]. These two findings appear to complement each other, suggesting a signaling role for b-catenin in animal axis formation. This issue is discussed in more detail by Barry Gumbiner in a separate review in this volume (pp 634-640). Whether the proposed p-catenin-associated signaling event is indeed separable from its role in cell adhesion, however, remains controversial.

Novel cadherin expression patterns

The differential expression patterns of multiple cadherins and their dynamic changes during development are the most fascinating features observed with this molecular family. Through their property of endowing, cells with selective adhesiveness, cadherins were proposed to control various morphogenetic events, such as cell sorting. The following are novel expression patterns for type I and II cadherins, which may provide us with new ideas for their developmental roles.

Cadherins in mesenchymal organization

Although the mesenchyme is a loose tissue, it expresses certain cadherins. For example, N-cadherin is involved in chondrocyte condensation and differentiation in chicken limb buds [42-44]. The expression pattern of cadherin-I1 (cad-ll), a type II class molecule also identified as OB-cadherin [45], was described [9*,46*,47*], and cad-11 turned out to be a major mesenchymal cadherin. In early mouse embryos, its strong expression


occurs in the cephalic mesoderm but not in the trunk paraxial mesoderm. In the latter, however, cad-l 1 begins to be expressed when somites form; the onset of this expression correlates with the segregation of each somite horn the presomitic mesoderm, suggesting a role for cad-11 in this segregation process. After the temporal expression of cad-11 in the entire somite unit, this cadherin disappears from the dermomyotome, leaving the sclerotome cad-l 1 -positive. At later developmental stages, cad-11 becomes expressed in a wide variety of mesenchymal tissues, in both mesodermal and neural crest derivatives. This cadherin, therefore, must be crucial for mesenchymal organization. M- and N-cadherin are expressed in another mesenchymal component, the muscle, and their developmental roles there have also been studied extensively [48-511.

Cadherins in migrating cells

One might think that migrating cells do not express cadherin, but this is not the case: even neural crest cells were demonstrated to express cadherins [lo**]. In the chicken embryo, the neural fold expresses cadherin-6B (c-cad6B, type II class), and its expression persists during the fusion of the neural folds, suggesting its role in the neural tube closure. This expression, however, ceases in migrating neural crest cells. They instead express cadherin-7 (c-cad7, type II class), but this expression occurs only in a subpopulation of cells. The c-cad7-positive subpopulation colonizes restricted tissues, including dorsal and ventral roots. None of the c-cad7-positive cells migrate towards the dermis, and only a few of them populate the dorsal root ganglia. As all migrating crest cells express TV.- and fi-catenin at cell-cell contact sites, all of them are assumed to express certain cadherins. In fact, N-cadherin is expressed in forming dorsal root ganglia, and cad-11 in cells differentiating into mesenchyme [9*,46*,47*]. Neural crest cells, therefore, seem to express cadherins in a subpopulation-specific manner; this might lead them to migrate as groups segregated from one another. It is tempting to speculate that the role of these cadherin expression patterns is to sort out heterogeneous crest cells during their migration and homing. Cadherin-mediated interaction may also be important for primordial germ cells, as they form clusters during migration [52]. Melanocytes in the epidermis, a neural crest derivative, were reported to express E-cadherin [53]. In this case, however, this cadherin is used for their attachment to the epidermis, as is the case for Langerhans cells [54].

The level of a-catenin localizing at the contacts between neural crest cells increases as these cells differentiate [lo**]. As this catenin is crucial for cadherin function, its upregulation may induce tighter cell-cell associations, and this process could be part of the control mechanism for the cessation of crest cell migration. L cells expressing an E-cadherin construct to which a-catenin was directly connected irreversibly adhere to their neighbors [55*]. The regulation of the association between cadherin

and a-catenin, therefore, could be a mechanism to control cell-cell attachment and detachment. It should be noted that C-cadherin activity is decreased upon activin-induced gastrulation of the mesoderm [56].

Roles of cadherins in neural morphogenesis The development of the nervous system requires numerous cell-cell recognition processes. One might ask whether cadherins as specific cell adhesion molecules can play any roles in such recognition processes. Although a number of cadherin subtypes are expressed in the nervous system, their expression is always regional except for the rather ubiquitous expression of N-cadherin in the early neural tube [57,58,59*,60,61*]. There are three categories of the regional cadherin expression pattern. First, the neural tube is regionalized by local cadherin expressions along the rostrocaudal or dorsoventral axis. The first example of this was the patchy E-cadherin expression found in the mouse embryonic brain [60]. A similar pattern was recently discovered for R-cadherin expression [61*]; in this case, R-cadherin delineated restricted neuromeres. Cell aggregation assays showed that the R-cadherin-positive neuroepithelial cells segregated corn negative cells in vitro, but only when the cadherins were active (H Matsunami, M Takeichi, unpublished data). This suggests that cadherins confer region-specific adhesiveness on neuroepithelial cells. It is likely that such cadherin expression patterns play a role in the segmentation of the neural tube by preventing cells from free migration at the boundaries between adjacent subdomains of the brain. In the second category, each of the sublayers of the neuroepithelium or cortex is specified by the expression of a particular cadherin. For example, N-cadherin expression was restricted to the subependymal zone in the adult canary neostriatum, and downregulated during neuronal differentiation and migration [62*]. Blocking of N-cadherin function with antibodies in this system facilitated neuronal cell body outgrowth from the subependymal zone. This type of cadherin expression may function to allocate a given cell population to particular sublayers of the neural tube.

The third category concerns clustering or wiring of neurons. N- and R-cadherin are expressed in discrete sets of nuclei constituting the chicken visual network [57]. Many other cadherins are also expressed in the brain, each in a subset of nuclei (Y Kimura, T Inoue, S Suzuki, T Tanaka, M Takeichi, unpublished data). These suggest that cadherins are involved in the formation of nuclei through their selective homophilic interactions. It is also possible that these cadherins are used for heterotypic neuronal connections. These arguments are, however, totally speculative at present. In the peripheral nervous system, E-cadherin is expressed in a subset of sensory neurons whose afferent fibers terminate in a specific zone of the dorsal horn. At the electron microscopic level, this E-cadherin is localized at lateral contacts between a subset of unmyelinated axons [63*]. This finding suggests that cadherins play a role


in selective fasciculation of axons. E-cadherin was also found to be expressed in Schwann cells. Interestingly, in this case, E-cadherin localizes to the ‘autotypic adherens junctions’ that are formed between plasma membrane wraps in a single Schwann cell [64*.]. In addition, the cadherin-associated protein aN-catenin was found to be preferentially expressed in differentiated parts of the nervous system [65*], suggesting that it has specific roles in neural cell connections.

Regulation of cadherin gene expression

Precise regulatory systems are required to orchestrate the complex expression patterns of cadherins. Fragmentary information about such systems is being accumulated. At the dorsal midline of the fetal brain, Wnt-1 sup- presses E-cadherin expression, but sustains aN-catenin expression, with both controls being exerted at the mRNA level [66*]. HoxD9 and HNF-1 activate the L-CAM promoter/enhancer in transient gene expression systems [67*]. Overexpression of ERBB2 in mammary epithelial cells inhibits E-cadherin gene transcription [68]. HGF was demonstrated to suppress E- and P-cadherin expression at the protein level in a cell line [69], and estradiol regulates E-cadherin mRNA level in the ovary [70]. Multiple factors are thus effective in the alteration of cadherin gene activities. The promoter activities of the human E-cadherin and mouse P-cadherin genes have also been described [71,72].

Conclusions

Classic cadherins have been found to function not only in vertebrate but also in invertebrate species, indicating the general importance of this molecular family for organization of multicellular systems. There are at least two possible ways for the cadherins to control animal morphogenesis. One is to regulate cell-cell contacts through their interaction with cytoplasmic proteins, although this point was only discussed briefly in this review. For example, chemical modification of catenins, release of the catenins from cadherin, and other types of cytoskeletal reorganization, can modulate cadherin-mediated adhesion. This kind of mechanism should be essential for various cell rearrangement processes such as occur in the epithelial-mesenchymal transition. The other way concerns the existence of a large number of cadherin subtypes with distinct adhesion specificity. It was proposed previously [15] that cadherin-mediated specific cell adhesion controls various types of cell sorting events during morphogenesis. The novel expression patterns of cadherins summarized in this article support this hypothesis. The differential expression of multiple cadherins in the nervous system is particularly intriguing, because it suggests that they

may be involved in neuronal recognition processes. In addition, cadherins were found to control not only physical cell-cell associations but also other cellular properties; several examples were discussed in this article. This finding suggests that this molecular family is involved in intercellular signaling networks. In the future, we must take into account other members of the cadherin superfamily, such as T-cadherin and protocadherins [l], whose functions are largely unknown at present. Uncovering their morphogenetic roles is another important goal that must be achieved in this field.

Acknowledgements

I thank Keiko Imai for her assistance in preparing the

manuscript, and Sayumi Shibamoto for critical reading of it. I also thank KM Yamada and JP Thiery for thoughtful dis-

cussion on cadherins. Our research on cadherins is supported

by a Grant-in-Aid for Creative Fundamental Research from the

Ministry of Education, Science, and Culture of Japan, and by

a grant from the Human Frontier Science Program.

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This study and 127.1 reports the effect of E-cadherin gene knockout on early mouse development.

29. Heasman J, Ginsberg D, Geiger B, Coldstone K, Pratt T, Yoshida-Noro C, Wylie C: A fimctional test for maternally inherited cadherin in Xenopus shows its importance in cell adhesion at the blast& stage. Development 1994, 120~49-57.

30. Levine E, Lee CH, Kintner C, Gumbiner BM: Selective disrup . Bon of E-cadherin function in early Xenopus embryos by a

dominant negative mutant. Development 1994, 120:901-909. The extracellular domain of E-cadherin can function as a dominant- negative construct when injected into Xenopus embryos.

31. Fujimori T, Takeichi M: Disruption of epithelial cell-cell adhesion’ by exogenous expression of a mutated non-functional N-cadherin. MO/ Biol Cell 1993, 437-47.

32. Dufour 5, Saint Jeannet JP, Broders F, Wedlich D, Thiery JP: * D~t~l pe~u~ti~s in the rno~h~ of anterior

structures induced by overexpression of truncated XB- and N- cadherins in Xenopus embryos. I Ceff Bioi 1994, 127:521-535.

Dominant-negative constructs of XB- and N-cadherin are not identical in their abilities in perturbing cadherin-mediated cell contacts.

33. Holt CE, Lemaire P, Curdon JB: Cadherin-mediated cell inter- . actions are necessary for the activation of MyoD in Xenopw

mesodenn. Proc Narl Acad Sci USA 1994, 91:10844-10848. Muscle differentiation is prohibited when a N-cadherin dominant- negative construct was injected in Xenopus embryos. This result provides evidence that cadherin-rn~iat~ cell-cell communication is involved in cell differentiation.

34. Hemriston ML, Gordon II: III vivo analysis of cadherin function . in the mouse intestinal epithelium: essential roles in adhesion,

maintenance of differentiation, and regulation of programmed cell death. / Cell Biol 1995, 129489-506.

A dominant-negative construct of N-cadherin was expressed in the intestinal epithelium by making transgenic mice. This expression caused multiple effects on enterocyte organization, including precocious entry into a death program.

35. l .

Marrs JA, Andersson-Fisone C, Jeong MC, Cohen-Gould L, Zur- zolo C, Nabi IR, R~riRuez-Boulan E, Nelson WI: Plasticitv in epithelial cell phenotype: modulation by expression of ‘different cadherin cell adhesion molecules. j Cell Biol 1995, 129:507-520.

Exogenous expression of E-cadherin in a retinal pigment cell line induced changes in cell polarity, accumulation of a different form of ankyrin, and desmosomal assembly, including accumulation of desmoglein mRNA.

36. Watabe M, Nagafuchi A, Tsukita S, Takeichi M: Induction of . polarized cell-cell association and retardation of growth by


activation of the E-cadherin-catenin adhesion system in a dis- 51. Cifuentes-Diaz C, Nicolet M, Coudou 0, Rieger F, Mege RM: persed carcinoma line. 1 Cell Biol 1994, 127~247-256. N-cadherin expression in developing, adult and denervated

Demonstrates that E-cadherin-a-catenin are essential for the junctional chicken neuromuscular system: accunudations at both the complex fo~ation. This study also showed that E-cadherin activity is neu~m~~ar junction and tbe node of Ran&r. Devetop- involved in cell growth control. men? 1994, 120:1-11.

37. Hodivala KJ, Watt FM: Evidence that cadherins piay a role in the downregulation of in&grin expression that occurs during keratinocyte terminal differentiation. f Cell Biof 1994, 124:589-600.

52. Comperts M, Garcia-Castro M, Wylie C, Heasman I: interactions between primordial germ cells play a role in their migration in mouse embryos. Development 1994, 120:135-l 41.

38. Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara T, . Nagafuchi A, Tsukita S, Shibamoto S, Ito F et al.: A truncated

bcatenin disrupts the interaction between E-cadherin and a- catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines. Cancer Res 1995, 54:6282-6287.

See annotation [39*1.

53. Tang A, Eller MS, Hara M, Yaar M, Hirohashi S, Gilchrest BA: E-cadherin is the major mediator of human melanqte adhesion to keratinocytes in vitro. / Cell Sci 1994, 107:983-992.

54. Tang A, Amagai M, Granger LC, Stanley JR, Udey MC: Adhe- sion of epidermal langerhans cells to keratinocytes mediated by E-cadherin. Nature 1993, 7:82-85.

39. Kawanishi J, Kato J, Sasaki K, Fujii 5, Watanabe N, Niitsu Y: . Loss of E-cadherin-dependent ceil-cell adhesion due to muta-

tion of the &catenin gene in a human cancer cell line, HSC-39. MO/ Cell Bio/ 1994, 15:1175-l 181.

This and 138.1 demonstrate that cells with a truncated form of p-catenin cannot normally adhere to one another. These are the first report of & catenin mutation in vertebrate cells.

55. Nagafuchi A, lshihara S, Tsukita S: The roles of catenins l in the cadherin-mediated cell adhesion: functional analysis

of E-cadhe&+-catenin fusion molecules. / Cell 5io/ 1994, 127:235-245.

Demonstrates that L cells transfected with cDNA encoding a E-cadherin- a-catenin fusion protein irreversibly adhere to one another or to other ceils.

40. Heasman J, Crawford A, Coldstone K, Gamer-Hamrick P, . . Gumbiner B, McCrea P, Kintner C, Yoshida NC, Wylie C:

Overexpression of cadherim and underexpression of &catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Ceil 1994, 79:791-803.

56. Brieher WM, Gumbiner BM: Regulation of C-cadherin function during activin induced morphogenesis of Xenopus animal caps. J Cell 5iof 1994, 126:519-527.

Suggests that depletion of &catenin affects dorsal differentiation in Xeno- pus embryos when cadherin activity is not fully blocked. Together with the results of [41**], this study suggests the presence of a signaling system mediated by pcatenin, which controls embtyonic axis formation.

57. Redies C, Engelhart K, Takeichi M: Differential expression of N- and R-cadherin in functional neuronal systems and other structures of the developing chicken brain. / Comp Neural 1993, 333:398-416.

41. Funayama N, Fagotto F, McCrea P, Gumbiner BM: fmbry- . . onic axis induction by the armadillo repeat domain of &

catenin: evidence for intracellular signaling. / Cell Biol 1994, 128:959-968.

58. Redies C, Muller H-AI: Similarities in structure and expression between mouse P-cadherin, chicken B-cadherin and frog XB/U- cadherin. Cell Adhesion Commun 1994, 2:51 l-520.

Overexpression of &catenin induces duplication of the embryonic axis in Xenopus. This study also shows that fi-catenin can be localized into the nuclei.

59. Murphy-Erdosh C, Napolitano EW, Reichardt LF: The expression . of B-cadherin during embryonic chick development. Dev Biol

1994, 161:107-125. First detailed analysis of l3-cadherin expression in chicken embryos.

42. Oberlender SA, Tuan RS: Expression and functional involvement of N-cadherin in embryonic limb chondrogenesis. De- ve/~me~~ 1994, 120: 177-l 87.

60. Shimamura K, Takeichi N: Local and transient expression of E-cadherin involved in mouse embryonic brain morphogenesis. ~ve~o~ment 1992, 116:1011-1019.

43. Oberlender SA, Tuan RS: ~tiotem~ral profile of N-cadherin expression in the developing limb mesenchyme. Cell Adhesion Commun 1994, 21521-537.

61. Ganzler Sll, Redies C: R-cadherin expression during nucleus . formation in chicken forebrain neuromeres. 1 Neurosci 1995,

15:in press.

44. Tsonis PA, Del Rio-Tsonis K, Millan JL, Wheelock MI: Expres- sion of N-cadherin and alkaline phosphatase in chick limb bud mesenchymal cells: regulation by 1,25-dihydroxyvitamin D3 or TCF-fll. Exp Cell Res 1994, 213:433-437.

R-cadherin expression pattern in the chicken forebrain correlates with the formation of a subset of neuromeres and nuclei.

45. Okazaki M, Takeshita S, Kawai S, Kikuno R, Tsujimura A, Kudo A, Amann E: Molecular cloning and characterization of OB- cadherin, a new member of cadherin family expressed in os- teoblasts. 1 Viol Chem 1994, 269:12092-12098.

62. Barami K, Kirschenbaum B, Lemmon V, Goldman SA: N-cad- . herin and Ng-CAM/8D9 are involved serially in the migration

of newly generated neurons into the adult songbird brain. Neu- ron 1994, 13567-502.

Antibodies to N-cadherin facilitate migration of cells from the subven- tricular zone to the upper layers.

46. Hoffmann I, Balling R: Cloning and expression analysis of l a novel mesodermally expressed cadherin. Dev 5iol 1995,

169:337-346. See annotation 19%

47. Simonneau L, Kitagawa M, Suzuki S, Thiery JP: Cadherin 11 l expression marks the rn~~~l phenotype: towards new

functions for cadherins? Cell Adhesion Commun 1995, 3:in pre%.

See annotation f9’1.

63. Uchiyama N, Hasegawa M, Yamashina T, Yamashita J, Shima- . mura K, Takeichi M: lmmunoelectron microscopic localization

of E-cadherin in dorsal root ganglia, dorsal root and dorsal horn of postnatal mice. / Nwrocytol 1994, 23~460-468.

E-cadherin is expressed at lateral contacts between axons derived from a subset of sensory neurons.

48. Bornemann A, Schmalbruch H: lmmunocytochemistry of M-cadherin in mature and regenerating rat muscle. Anat Ret 1994, 239:119-125.

64. . .

Fannon AM, Sherman DL, tlyina-Gragerova C, Trophy PJ, Friedrich VL Jr, Colman DR. Novei E-Turin-rn~iat~ adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions. ) CeN Biof 1995, 129:189-202.

E-cadherin was localized to a specific type of adherens junctions in Schwann cells. This is the first demonstration that cadherins form junctions between plasma membrane components present in a single cell.

49. lrintchev A, Zeschnigk M, Starzinski-Powitz A, Wernig A: Ex- pression pattern of M-cadherin in normal, denervated, and regenerating mouse muscles, Dev Dyn 1994, 199~326-337.

50. Soler AP, Knudsen KA: N-cadherin involvement in cardiac myocyte interaction and myofibrillogenesis. Dev Biol 1994, 124729-741.

65. Uchida N, Shimamura K, Miyatani S, Copeland NG, Gilbert . DJ, Jenkins NA, Takeichi M: Mouse aN-catenin: two isoforms,

specific expression in the nervous system, and chromosomal localization of the gene. Dev Viol 1994, 163:75-85.

c,N-catenin is almost exclusively expressed in the nervous system in fetal mice.


66. Shimamura K, Hirano 5, McMahon AP, Takeichi M: Wnt-l- . dependent regulation of local E-cadherin and aN-catenin ex-

pression in the embryonic mouse brain. ~~~~~t 1994, 120:2225-2234.

First in v&o analysis of the effect of Wnt-1 mutations on cadherin-catenin expression. in Wnt-1 mutated mice, E-cadherin ,is- upregulated and aN-catenin is downregulated at the midline regions of the embryonic brain.

67. Goomer RS, Holst BD, Wood IC, Jones FS, Edelman GM: l Regdation in vitro of an L-CAM enhancer by homeobox

genes HoxD9 and HNF-1. Proc /Vat/ Acad Sci USA 1994, 91:7985-7989.

70.

71.

Demonstrates the possibiiity that HoxD9 and HNF-1 are regulators of cadherin expression.

68. D‘Souza B, Taylor-Papadim;tri~ J: Dverexpression of ERBBZ in human mammary epithelial ceils signals inhibition of transcrip tion of the E-cadberin gene. Proc Nat/ Acad Sci USA 1994,

72.

and P-cadherin in gastric carcinoma cell lines. virchows Arch 1994, 425:139-l 44.

MacCalman CD, Farookhi R, Blaschuk OW: Estradiol regulates E-cadherin mRNA leves in the surface epithelhnu of the mouse ovary. Clin Exp Metastasis 1994, 12:276-i-282.

Bussemakers MJ, Ciroldi tA, Van Bokhoven A, Schalken JA: Transcriptional regulation of the human E-cadherin gene in human prostate cancer cell lines: characterization of the human E-cadherin gene promoter. Biochem Siophys Res Commun 1994, 2031284-l 290.

Hatta M, Takeichi N: Complex cell type-specific transcriptional regulation by the promoter and an intron of the mouse P-cadherin gne. Dev Growth Differentiation 1994, 36:509-519.

91:7202-7206.

69. Tannapfel A, Yasui W, Yokoraki H, Wittekind C, Tahara E: M Takeichi, Department of Biophysics, Faculty of Science, Kyoto Effect of hepatocyte growth factor on the expression of E- University, Kitashirakawa, Sakyo-ku, Kyoto 606-01, Japan.

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