cadherins in development: cell adhesion, sorting, and tissue...

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Cadherins in development: cell adhesion,sorting, and tissue morphogenesisJennifer M. Halbleib and W. James Nelson1

Departments of Biological Sciences and Molecular and Cellular Physiology, Stanford University,Stanford, California 94305, USA

Tissue morphogenesis during development is dependenton activities of the cadherin family of cell–cell adhesionproteins that includes classical cadherins, protocadher-ins, and atypical cadherins (Fat, Dachsous, and Fla-mingo). The extracellular domain of cadherins containscharacteristic repeats that regulate homophilic and het-erophilic interactions during adhesion and cell sorting.Although cadherins may have originated to facilitatemechanical cell–cell adhesion, they have evolved tofunction in many other aspects of morphogenesis. Theseadditional roles rely on cadherin interactions with awide range of binding partners that modify their expres-sion and adhesion activity by local regulation of the ac-tin cytoskeleton and diverse signaling pathways. Herewe examine how different members of the cadherin fam-ily act in different developmental contexts, and discussthe mechanisms involved.

Cadherins were originally identified as cell surface gly-coproteins responsible for Ca2+-dependent homophiliccell–cell adhesion during morula compaction in the pre-implantation mouse embryo and during chick develop-ment (Yoshida and Takeichi 1982; Gallin et al. 1983;Peyrieras et al. 1983). Subsequently, >100 family mem-bers have been identified with diverse protein structures,but all with characteristic extracellular cadherin repeats(ECs) (Nollet et al. 2000). Cadherins are important inboth simple and complex organisms. In addition to ver-tebrates, insects, and nematodes, members of the cad-herin family are found in unicellular choanoflagellates(King et al. 2003), the diploblast Hydra (Hobmayer et al.2000), and the sponge Oscarella carmela (Nichols et al.2006).

In the three decades since their discovery, it has be-come clear that the role of cadherins is not limited tomechanical adhesion between cells. Rather, cadherinfunction extends to multiple aspects of tissue morpho-genesis, including cell recognition and sorting, boundaryformation and maintenance, coordinated cell move-

ments, and the induction and maintenance of structuraland functional cell and tissue polarity. Cadherins havebeen implicated in the formation and maintenance ofdiverse tissues and organs ranging from polarization ofsimple epithelia, to mechanically linking hair cells inthe cochlea, to providing an adhesion code for neuralcircuit formation during wiring of the brain (Yagi andTakeichi 2000; Gumbiner 2005). Given the breadth oftheir functions, it is not surprising that defective cad-herin expression has also been linked directly to a widevariety of diseases including the archetypal disruption ofnormal tissue architecture, metastatic cancer (Berx andVan Roy 2001).

The large size of the cadherin family and the structuraldiversity of its members may have evolved to enable themany types of cell interactions required for tissue mor-phogenesis in complex organisms. The number of cad-herins as well as distinct features of their gene structurepermit precise temporal and spatial transcriptional regu-lation of cadherin subtypes, and variations in proteinstructure, particularly the cytoplasmic domain, facilitateinteractions that result in both specific modulation ofcadherin activity and initiation of intracellular signalingcascades in response to adhesion.

In this review, we focus on the three types of cadherinsand their roles in development: classical cadherins, pro-tocadherins, and atypical cadherins involved in planarcell polarity (PCP). We examine the distributions andfunctions of cadherins in the formation and maintenanceof tissues, and the mechanisms thought to be importantin regulating cadherin activity. Note that our knowledgeof each of these cadherin family subtypes is not equiva-lent, and by necessity we focus more on the classicalcadherins, although this knowledge may provide aframework for understanding other subtypes in the fu-ture.

Classical cadherins

Classical cadherins were the first subtype of the cadherinfamily identified, and structure/function studies haveprovided detailed insights into their molecular regula-tion. Cadherins are expressed in almost all vertebratetissues, form primarily homophilic cell–cell interac-tions, are often concentrated in the adherens junction

[Keywords: Cadherin; protocadherin; embryogenesis; cell sorting; tissuedifferentiation]1Corresponding author.E-MAIL [email protected]; FAX (650) 725-8021.Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1486806.

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(AJ), and appear to modulate adhesion through dynamicinteractions with the actin cytoskeleton.

Regulation of cadherin expression and activity

Structural and functional organization of the extracel-lular domain Classical cadherins, which are subdi-vided into type I and type II, have five ECs in the extra-cellular domain (Fig. 1). Type I classical cadherins medi-ate strong cell–cell adhesion and have a conserved HAVtripeptide motif in the most distal EC (EC1). They in-clude epithelial (E) and neuronal (N) cadherin, amongothers. In contrast, type II classical cadherins, such asvascular epithelium (VE) cadherin, lack this motif. TheEC1 domain is important for homophilic adhesion andcontains conserved tryptophan residues that are respon-sible for trans-cadherin binding (Nose et al. 1988; Chenet al. 2005; Patel et al. 2006), although heterophilic in-teractions between classical cadherins have also been re-ported (Shimoyama et al. 2000; Niessen and Gumbiner2002; Foty and Steinberg 2005). Other EC domains ofindividual family members specify interactions withother binding partners, which translates into uniquefunctionality; for example, the EC4 domain of N-cad-herin binds fibroblast growth factor receptor (FGFR) andactivates downstream signaling by FGFR (Fig. 2; Willi-ams et al. 2001).

Structural and functional organization of the cytoplas-mic domain The cytoplasmic domain is highly con-served between different subtypes of classical cadherinsand binds directly to several cytoplasmic proteins in-cluding �-catenin and p120 (Fig. 2). Cytoplasmic bindingpartners affect classical cadherin interactions with theactin cytoskeleton. p120 may regulate the cadherin–ac-tin cytoskeleton nexus directly by binding and inhibitingRhoA (Anastasiadis and Reynolds 2001) and indirectlyactivating Rac1 and Cdc42 via Vav2 (Noren et al. 2000),while stabilizing cadherins at the cell surface (Davis etal. 2003). �-Catenin, which also functions as a cotrans-criptional activator with the T-cell factor (TCF) family oftranscription factors (Brembeck et al. 2006), binds di-rectly to �-catenin (Aberle et al. 1994), which in turn isan actin filament-binding/bundling protein that also in-teracts with other actin-binding proteins (Kobielak andFuchs 2004).

These protein–protein linkages have lead to the con-clusion that �-catenin links cadherins to actin, eventhough most are based on binary interaction data. How-ever, it was recently shown using a combination of directbinding studies with purified proteins and measurementof protein dynamics in live cells that �-catenin does notinteract with �-catenin and filamentous actin simulta-neously (Drees et al. 2005; Yamada et al. 2005). Instead,�-catenin behaves in an allosteric manner, dependent onthe formation of either an �-catenin monomer that bindsstrongly to �-catenin or a homodimer that binds stronglyto actin (Drees et al. 2005). In addition to binding actin,�-catenin homodimers inhibit binding of the actin-nucleating Arp2/3 complex to actin filaments andthereby suppress actin polymerization (Drees et al.2005). �-Catenin also recruits formin-1, which acts tonucleate unbranched actin cables, to AJs (Kobielak et al.2004). This may be important in regulating actin dynam-ics at cell–cell contacts. Cells form transient contactsmediated by cadherins present on highly dynamic lamel-lipodia extensions (Adams et al. 1998) that are driven byArp2/3-mediated polymerization of branched actin net-works (Pollard and Borisy 2003). As the contact matures,cadherins become concentrated between opposed cellsurfaces, lamellipodial movements slow and eventuallycease as a stable cell–cell contact is established (Ehrlichet al. 2002; Vaezi et al. 2002), and actin filaments adja-cent to mature AJs become organized into unbranchedbundles parallel to the membrane (Hirokawa et al. 1983).Thus, the suppression of Arp2/3-mediated lamellipodiaactivity, and the concomitant localization of formin-1and formation of unbranched actin bundles at cell–cellcontacts could be coordinated by �-catenin.

Dynamic cell movements rely on actomyosin activity(Dawes-Hoang et al. 2005), and it has been assumed thatthis occurs at the level of the AJ (Wessells et al. 1971) andinvolves cadherins (Gates and Peifer 2005). If the cadher-in–catenin complex does not interact directly with actin,what anchors actin in the AJ? �-Catenin binds severalactin-binding proteins that could link the cadherin–catenin complex to the actin cytoskeleton, althoughthese have been shown as binary interactions and not inthe molecular context of a complex with cadherin andactin (Weis and Nelson 2006). An additional candidateprotein is Shroom, a PDZ domain-containing actin-bind-ing protein required for neural tube morphogenesis that

Figure 1. Cadherin structure. All cadherinspossess calcium-binding EC repeats of vary-ing number. Nonclassical cadherins also haveadditional extracellular motifs including lam-inin and EGF domains and flamingo boxes.Cadherins are single membrane-spanning pro-teins with the exception of flamingo, which isa seven-pass membrane protein. The cyto-plasmic tail of classical cadherins is con-served, but is different from that of protocad-herins and atypical cadherins. Brackets indi-cate that protocadherins have either six orseven ECs. Note that the represented size ofeach domain is not to molecular scale.

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localizes to AJs (Hildebrand 2005). Another is Vezatin,an AJ transmembrane protein that may link myosin tothe cadherin–catenin complex (Kussel-Andermann et al.2000). Also, a recent report identified an interaction be-tween the synaptotagmin-like protein Bitesize (Btsz) andMoesin, an actin-binding member of the Ezrin–Radixin–Moesin (ERM) family of cytoskeletal proteins; signifi-cantly, Btsz mutants fail to establish proper actin orga-nization at AJs during Drosophila cellularization (Pilotet al. 2006). Further studies are required to investigatehow the cadherin–catenin complex is functionallylinked to these modifiers at the actin cytoskeleton.

Regulation of cadherin expression Classical cadherinexpression is regulated at many levels including geneexpression and transport to, and protein turnover at thecell surface (Fig. 3).

Cadherin transcription is directly regulated by meth-ylation and repression of promoter activity (Fig. 3).Methylation is a common modification of DNA medi-ated by a family of DNA methyltransferase enzymes thatcatalyze the addition of a methyl group to cytosine resi-dues at CpG dinucleotides (Richards 2006). During car-cinogenesis, methylation of the E-cadherin promoter isassociated with reduced E-cadherin expression, and withdisease progression and metastasis (Strathdee 2002). Sev-eral classical cadherin genes also possess an unusuallylarge second intron (in humans, the size of intron 2 com-pared to total gene size for E-cadherin and N-cadherin are63 kb to 98 kb and 134 kb to 245 kb, respectively), whichhas been shown for E-cadherin to contain regulatory el-ements that modulate overall cadherin levels and tissue-specific expression during development (Stemmler et al.2005). Zinc finger proteins of the Slug/Snail family and

Smad-Interacting Protein (SIP1) are repressors of E-cad-herin gene transcription (Cano et al. 1996; Batlle et al.2000; Comijn et al. 2001; Conacci-Sorrell et al. 2003).Decreased E-cadherin gene transcription results in a lossof cell–cell adhesion and increased cell migration (Thiery2002), as well as accumulation of cytoplasmic, signaling-competent �-catenin that may function independentlyof, or synergize with Wnt signaling (Ciruna and Rossant2001). Slug may be a target gene of the TCF/�-catenincomplex (Conacci-Sorrell et al. 2003) that also binds toand represses the E-cadherin promoter (Jamora et al.2003). Thus, repression of cadherin expression by Slug/Snail/SIP1 or TCF/�-catenin complex may not only re-duce cell–cell adhesion, but the concomitant increase incytoplasmic �-catenin may lower the activation thresh-old of the Wnt pathway.

Transport of newly synthesized E-cadherin to theplasma membrane requires binding of �-catenin (Chen etal. 1999), and once delivered to the cell surface E-cad-herin is regulated by phosphorylation, ubiquitination,and proteolysis (Fig. 3). The structural integrity of thecadherin/catenin complex is positively and negativelyregulated by phosphorylation. Three serine residues inthe E-cadherin cytoplasmic domain (S684, S686, S692)are phosphorylated by Casein Kinase-II (CKII) and glyco-gen synthase kinase-3� (GSK3�), which generates addi-tional interactions with �-catenin resulting in a largeincrease in affinity between the two proteins (Huber andWeis 2001). In contrast, tyrosine phosphorylation of�-catenin at Y489 or Y654 disrupts binding to E-cad-herin, and at Y142 binding to �-catenin; tyrosine phos-phorylation of �-catenin is balanced by protein tyrosinephosphatases that stabilize �-catenin–E-cadherin inter-actions (Lilien and Balsamo 2005).

Figure 2. Cadherin-binding partners. Inaddition to extracellular homophilic (andsome heterophilic) trans binding, classicalcadherins interact intracellularly with thecatenins p120 and Hakai, which regulatethe actin cytoskeleton and cadherin endo-cytosis. N-cadherin also binds FGFR. Pro-tocadherins exhibit weak homophilic ad-hesion. The cytoplasmic domains of pro-tocadherins bind phosphatases, microtubule-destabilizing proteins, and chromatin re-modeling factors. Pcdh-�s also interactswith the Fyn tyrosine kinase, Reelin re-ceptor, and integrins in vitro. The cyto-plasmic domain of Fat interacts directlywith Atrophin transcriptional corepres-sors and members of the Ena/Vasp familyof actin regulators. The extracellular do-main of Fat may form homophilic adhe-sions, or heterophilic adhesions with Ds.Ds and Fmi may be linked to the cytoskel-eton. Interactions that have not beenshown definitively in vivo are indicatedwith a question mark. Brackets indicatethat protocadherins have either six orseven ECs. Note that the represented sizeof each domain is not to molecular scale.

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Cadherin-mediated cell–cell adhesion is modulated bychanges in the level of cadherin on the cell surface (Dug-uay et al. 2003; Foty and Steinberg 2005). Cadherins aretargets of ADAM (a disintegrin and metalloprotease do-main) 10 (Maretzky et al. 2005; Reiss et al. 2005) thatcleaves the cadherin extracellular domain close to thetransmembrane domain (Fig. 3). The resulting extracel-lular fragment could further disrupt adhesion by compet-ing with trans interactions between full-length cadherincomplexes (Wheelock et al. 1987). The cytoplasmic do-main of classical cadherins is also the target for proteo-lytic cleavage by the �-secretase activity of Presenilin-1(PS1), which results in a loss of cell–cell adhesion (Fig. 3;Marambaud et al. 2002); it has also been reported thatthe released cytoplasmic fragment binds the cAMP re-sponse element-binding protein (CREB)-binding protein(CBP), a scaffold for activating transcriptional modula-tors of the CREB basal transcription complex, and targetsit for degradation (Marambaud et al. 2003). E-cadherin isactively endocytosed via clathrin-coated vesicles (Bryantand Stow 2004), which can result in rapid loss of cell–celladhesion. It is targeted for internalization followingubiquitination by the E3 ubiquitin ligase Hakai (Figs. 2,3; Fujita et al. 2002) and other pathways that involvedisruption of the cadherin–catenin complex by tyrosinekinases (Kamei et al. 1999; Avizienyte et al. 2002). Cad-herin stability at the cell surface is also regulated byp120 as loss of cadherin–p120 binding results in rapidendocytosis of the E-cadherin complex (Fig. 3; Davis etal. 2003).

The extensive transcriptional and post-transcriptionalregulation of cadherins suggests that the level of cad-herin cell surface expression and the maintenance oflinkage to intracellular binding partners (controlled per-

haps by additional signaling cascades) modify cadherinactivity. This is further supported by experiments in fi-broblasts expressing different cadherins that show sort-ing out of mixed cell populations is mediated by surfaceexpression levels of cadherins (Duguay et al. 2003; Fotyand Steinberg 2005). Thus, it appears that cell sorting canbe mediated by differences in levels of cadherin cell sur-face expression as well as subtype (see below). Recently,validation of these regulatory mechanisms within thedevelopmental context of tissue morphogenesis has beenestablished in Drosophila. In the fly eye, requirement ofasymmetrical localization of Drosophila neuronal (DN)-cadherin for proper cone cell morphology has beenshown (Hayashi and Carthew 2004). Intriguingly, regu-lated endocytosis and recycling of cadherins controlledby PCP components appears to be necessary for hexago-nal wing cell packing (Classen et al. 2005). These resultsdemonstrate in vivo two distinct mechanisms to facili-tate cell sorting by regulating the level and localizationof cadherin surface expression.

Cadherin expression and function in development

Classical cadherins in cell sorting Each subtype ofclassical cadherin tends to be expressed at the highestlevels in distinct tissue types during development. Forexample, in addition to being present at the morula stageof embryogenesis, E-cadherin is expressed in all epitheliaand is important for establishing and maintaining apico–basal polarity (Fig. 4E); N-cadherin is expressed in neuraltissue and muscle; R-cadherin is expressed in the fore-brain and bone; P-cadherin is present in the basal layer ofthe epidermis; and, VE-cadherin is expressed in endothe-lial cells (for details of cadherin subtype expression pat-terns see Takeichi 1988; Hirano et al. 2003). Other clas-sical cadherins such as Cadherin-6 and Cadherin-11 areexpressed preferentially in the kidney and mesoderm,respectively (Nollet et al. 2000). However, it is also clearthat there is overlap in the tissue distributions of classi-cal cadherins such that E-cadherin, for example, is ex-pressed in the nervous system (Takeichi 1988).

These tissue expression patterns of cadherin subtypes,in conjunction with their homophilic adhesive proper-ties, may facilitate sorting of specific cell types into tis-sues. The role of cadherin subtypes in mediating cellsorting has been shown in tissue culture using nonad-herent fibroblasts exogenously expressing different cad-herins (Fig. 4A,B; Nose et al. 1988; Foty and Steinberg2005). Cadherin-mediated cell sorting was shown to bephysiologically relevant in Drosophila oogenesis whenthe oocyte is localized to the posterior of the germlinecyst by homophilic interactions between the Drosophilafunctional homolog of E-cadherin, DE-cadherin, ex-pressed by both the oocyte and posterior follicle cells(Godt and Tepass 1998). It has subsequently been ob-served in a variety of developmental contexts includingXenopus gastrulation and vertebrate limb formation(Gumbiner 2005). Other studies have also emphasizedthe importance of homophilic adhesion of cadherins incell sorting. Overexpression of Cadherin-6B or Cad-

Figure 3. Regulation of cadherins. Classical cadherins (bluescheme) are transcriptionally regulated by zinc-finger transcrip-tion factors such as Snail and Slug, and promoter methylation.Exocytosis of newly synthesized protein from the endoplasmicreticulum to the cell surface is dependent on binding to�-catenin. Cadherin levels at the cell surface are regulated byendocytosis upon Hakai-mediated ubiquitination subsequent touncoupling from catenins following phosphorylation; cadherincan be cleaved by ADAM10, MMPs, or PS1. Protocadherins (or-ange scheme) at the plasma membrane can be sequentiallycleaved by ADAM10 and PS1. In the case of Pcdh-�, the result-ing fragment localizes to the nucleus and can activate transcrip-tion of the Pcdh-� gene cluster.

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herin-7 in Purkinje cell progenitors resulted in their pref-erential redistribution to regions of the cerebellum thatexpress the respective cadherin endogenously (Luo et al.2004). In the mouse telencephalon, a compartmentboundary is established between the primordia of thecerebral cortex and the striatum comprising complemen-tary expression patterns of R-cadherin and Cadherin-6.Expression of either exogenous Cadherin-6 or R-cadherinin cells located in the vicinity of the boundary inducedstrong preferential sorting of cells across the presump-tive boundary into the Cadherin-6 or R-cadherin positivecompartment, respectively (Inoue et al. 2001). It has alsobeen postulated that expression of N-cadherin in tumorcells acts as a targeting mechanism for endothelial andstromal tissue during metastasis (Hazan et al. 2000; DeWever et al. 2004; Qi et al. 2005).

Studies of cell sorting in the lumbar spinal cord ofchick embryos has provided further insights into theroles of different cadherins and the importance of theEC1 domain. Differences in the distributions of six cad-herins in the lateral motor column occur concurrentlywith the segregation of neurons into different motorpools. Misexpression of one of these cadherins, MN-cad-herin, but not another (Cadherin-6B), resulted in incor-rect mixing of motor pools (Price et al. 2002). This indi-cates that the expression and homophilic adhesion ofMN-cadherin-expressing cells controls the formation ofdiscrete neuronal clusters in the lateral motor column.Significantly, replacing the EC1 domain of Cadherin-6Bwith that of MN-cadherin was sufficient to confer onCadherin-6B the ability to (mis-) sort neurons into motorpools similar to misexpressing MN-cadherin (Price et al.2002; Patel et al. 2006). This result provides physiologi-cally relevant evidence that the EC1 domain is a criticaldeterminant of the specificity of cadherin adhesion incell sorting.

Although specificity of adhesion by EC1 provides onemechanism to explain how cells segregate from eachother within complex cell mixtures, an explanation oftissue development induced by different cadherins ex-

pressed in embryonic stem cells (ESCs) is not as straight-forward. Larue et al. (1996) showed that ESCs isolatedfrom E-cadherin−/− preimplantation embryos failed todifferentiate into any organized structure when inducedto form teratomas in mice; in contrast, ESCs from E-cad-herin+/− or wild-type embryos formed many different tis-sues. Strikingly, E-cadherin−/− ESCs expressing E-cad-herin or N-cadherin transgenes formed teratomas witheither epithelial or neuroepithelial structures, respec-tively (Larue et al. 1996); rescue with Cadherin-11yielded teratomas with bone and cartilaginous structures(Kii et al. 2004). These results imply that individual cad-herin subtypes instruct the differentiation of specific tis-sues, and perhaps suppress the differentiation of others.The mechanisms involved are unknown. For example, itis unclear whether the effect could be due to differencesin adhesion strength or cell sorting mediated by the ex-tracellular domain of each cadherin transgene. That eachcadherin might activate tissue-specific intracellular sig-naling pathways seems to be at variance with the highsequence similarity and conserved binding partners ofthe cytoplasmic domain of all of these cadherins (seeabove). However, differential activation via the extracel-lular domain would not be unprecedented, consideringthe subtype-specific binding of N-cadherin to FGFR andsubsequent downstream signaling (Williams et al. 1994).In this context it is interesting to note that studies ofXenopus trunk mesoderm patterning found that whiledisruption of cell–cell adhesion results in tissue disorga-nization, modulation of �-catenin activity was respon-sible for cell sorting at the individual cell level (Reintschet al. 2005).

Cadherin subtype switching in development Subtypeswitching is a prominent physiological feature of cad-herin morphogenetic function during development. Thefirst of these occurs during gastrulation and results in achange in cadherin expression from DE-cadherin to DN-cadherin in the developing Drosophila mesoderm (Odaet al. 1998). A similar conversion from E-cadherin to N-

Figure 4. Developmental roles of cadherins. (A) Cad-herins mediate Ca2+-dependent cell–cell adhesion. (B)Differential expression of cadherins (either by modulat-ing subtype or expression level) induces sorting out ofmixed cell populations. (C) Cadherin subtype switchingoccurs during coordinated cell movements such as neu-rulation, where the invaginating neural plate expressesN-cadherin, while the overlying ectoderm expresses E-cadherin. (D) Cadherins function in PCP. Ds and Fatinteract directly and are upstream of Fz, while Fmifunctions downstream, leading to additional expressionof PCP components and asymmetrical localization ofproteins including Fz, Disheveled (Dsh), Van Gogh(Vang), and Prickle (Pk) (Klein and Mlodzik 2005). Clas-sical cadherins have specialized distributions at the AJ(light-blue arrows) of polarized epithelia (E), and atpuncta adherentes (blue arrows) that surround the ac-tive zone at the neuronal synapse (F). (TJ) Tight junc-tion; (AJ) adherens junction.






cadherin is observed during neurulation in chick em-bryos (Fig. 4C; Hatta et al. 1987). In both cases, the pre-viously well-ordered tissue type acquires (D)N-cadherinexpression prior to a major morphological movement.Cells lose their epithelial morphology, convert to a fi-broblastic shape, and acquire the ability to delaminatefrom the tissue and migrate, a process known as epithe-lial–mesenchymal transition (EMT).

EMT is best-studied in the context of tumor progres-sion (Maeda et al. 2005). As the pathological and embry-onic processes involved in EMT are similar, results ob-tained from studies of tumor progression can give insightinto the mechanisms of EMT in developmental contexts.During tumor progression, E-cadherin or Cadherin-13(also known as H-cadherin or T-cadherin) are down-regu-lated, and concomitantly the expression of N-cadherin,R-cadherin, Cadherin-6, or Cadherin-11 is increased (Is-lam et al. 1996; Shimazui et al. 1996; Johnson et al.2004). These switches in cadherin expression are associ-ated with increased invasion and poor prognosis (Paul etal. 1997). Interestingly, breast cancer cells forced to ex-press both E-cadherin and N-cadherin are as invasive asthose expressing N-cadherin alone, suggesting that dif-ferential adhesive properties between cadherins are notsufficient to mediate the change in motility (Nieman etal. 1999). N-cadherin binds directly to, and activatesFGFR (Fig. 2; Williams et al. 1994), leading to mitogen-activated protein kinase-extracellular signal-regulatedkinase (MAPK-ERK) signaling and metalloproteinase(MMP) induction (Suyama et al. 2002). MMP-3 cleavesthe extracellular domain of E-cadherin, providing a po-tential mechanism for functional inactivation of E-cad-herin upon N-cadherin expression (Xian et al. 2005).

Roles of classical cadherins in dynamic cell movementsTissues expressing E-cadherin also undergo cell morpho-genetic movements involving convergence and exten-sion through radial and mediolateral intercalation duringepiboly and gastrulation, respectively. When E-cadherinadhesion is disrupted during Zebrafish epiboly, epiblastsstill intercalate but are not stabilized in the externallayer and often deintercalate (Kane et al. 2005; Shimizuet al. 2005). Intercalation during gastrulation involvesremodeling of AJs to expand cell–cell adhesions in oneplane of the epithelium and contract them in the per-pendicular plane (Bertet et al. 2004). This process isthought to require interactions between actin filaments,Myosin II, and the AJ like those that occur during apicalconstriction in cell morphogenesis (Dawes-Hoang et al.2005), although it is not clear how actomyosin is directlyanchored to the AJ (see above).

Classical cadherins in orientation of the plane of celldivision Analysis of the roles of cadherins in spreadingand intercalation revealed that E-cadherin can alsospecify the plane of cell division. Regulating cell divisionalong one axis permits directional expansion of tissues(Lu et al. 2001; Wang et al. 2004). Cadherins appear toregulate the plane of cell division in several cellular con-texts. In the Drosophila testis, germ stem cell (GSC) mi-

tosis gives rise to a stem cell and a gonialblast. Mainte-nance of the GSC population requires the proper orien-tation of the division plane, which is determined bycadherin-dependent adhesion between GSCs and the“hub,” a cluster of somatic cells (Yamashita et al. 2003).Cadherin-mediated cell adhesion may also be importantin polarized division of mammalian hematopoietic stemcells (HSCs) as N-cadherin localizes asymmetrically be-tween long-term HSCs and spindle-shaped osteoblastcells (Zhang et al. 2003). Another example is the role ofthe AJ in the regulation of neuroblast delamination fromthe neuroectoderm in Drosophila development (Wodarz2005). The neuroblast retains contacts with the neuro-ectoderm through the AJ, which positions important po-larity cues to the apical domain, while determinants ofthe ganglion mother cell fate are located in the basaldomain of the dividing cell.

Classical cadherins in organization and function of thenervous system The development and maintenance ofthe nervous system are major areas of focus in the studyof classical cadherins, as (1) different cadherins are ex-pressed in different cells and regions of the nervous sys-tem, (2) dynamic cadherin adhesion is important in neu-rite outgrowth and guidance and synapse formation, and(3) cadherins can regulate synaptic plasticity.

Specific classical cadherins localize to different re-gions of the embryonic brain and peripheral nervous sys-tem (Hirano et al. 2003), and disruption of cadherin ex-pression results in cell mixing at domain boundaries(Stoykova et al. 1997; Inoue et al. 2001). Although thereis no obvious functional correlation between neuronswithin a particular region and the cadherins expressed inthat region, as development proceeds several cadherinsbecome restricted to specific circuits within the CNS(Suzuki et al. 1997). In other cases, multiple cadherinsare expressed in one brain region that receives informa-tion from (Arndt et al. 1998; Redies et al. 2000) or sendsinformation to several neuronal structures (Redies et al.1993; Wohrn et al. 1999), suggesting in this case a role forcadherins in the control of cell–cell networks involved inthe transmission of different signals.

Cadherins facilitate circuit formation during growthcone navigation and path-finding by controlling axon fas-ciculation and targeting. Neuronal classical cadherinsare expressed in distinct axonal tracts in Drosophila andthe chick embryo, and loss of function results in dis-rupted fasciculation (Iwai et al. 1997; Honig et al. 1998).In addition, N-cadherin and R-cadherin expressionstimulates neurite outgrowth at least partially by acti-vating FGFR (see above) (Redies et al. 1992; Riehl et al.1996), while Cadherin-11 promotes axon elongation(Marthiens et al. 2005) and Cadherin-13 acts as a repel-lant cue for growth cones (Fredette et al. 1996). There issome evidence that cadherins also function as axonaltargets in both the chick and Drosophila (disruption ofN-cadherin adhesion results in mistargeting of axons inthe visual systems of both organisms [Inoue and Sanes1997; Lee et al. 2001]), but a widespread function of cad-herins in targeting has not been established definitively

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as the target brain region and growing axon often do notexpress the same cadherin (Shimamura et al. 1992), andfiber projection is normal in Cadherin-11-deficient mice(Manabe et al. 2000). However, recent work has impli-cated N-cadherin-mediated adhesion in neurogenesis fol-lowing injury (Chen et al. 2006), indicating that morework is required to define the role of cadherins in circuitformation.

There is increasing evidence for a role of classical cad-herins in the formation of individual synapses. N-cad-herin is one of the first proteins to localize to most na-scent synapses (Fannon and Colman 1996; Uchida et al.1996; Benson and Tanaka 1998), and a synaptic localiza-tion of other cadherins, including R-cadherin and Cad-herin-7, has been found (Heyers et al. 2004). As develop-ment proceeds, N-cadherin becomes restricted to excit-atory terminals (Benson and Tanaka 1998), raising thepossibility that expression of specific cadherin subtypesmight be instructive in synapse function. Interestingly,loss of N-cadherin in mice has no effect on the initiationof neurulation, although malformations of the neuraltube occur (Radice et al. 1997), and blocking N-cadherinfunction with dominant-negative constructs does not re-sult in neurite outgrowth abnormalities, but leads to al-tered dendritic spine morphology and synapse densityconcomitant with a loss of �-catenin from spines (Toga-shi et al. 2002). A similar phenotype is observed whenneuronal-specific �N-catenin is deleted, suggesting cad-herins may affect spine morphology through regulationof the actin cytoskeleton (Abe et al. 2004). At maturesynapses, cadherins form junctions (puncta adherentes)that surround the active zone from which neurotrans-mitter release occurs (Fig. 4F; Fannon and Colman 1996;Uchida et al. 1996).

Although cadherins may play only a structural role atsynapses, they have been implicated in neuronal func-tion through regulation of synaptic plasticity. Depolar-ization of excitatory neurons results in increased N-cad-herin-mediated adhesion (Tanaka et al. 2000), as doesstimulation designed to induce long-term potentiation(LTP) (Bozdagi et al. 2000). Intriguingly, LTP can beblocked with antibodies against the extracellular domainof N-cadherin or E-cadherin, neither of which effect nor-mal synaptic function (Tang et al. 1998). Reduced Cad-herin-11 levels have also been reported to stimulate LTP(Manabe et al. 2000). Whether these effects are due tocadherin-mediated changes in the distance between pre-and post-synaptic terminals or the width of synapses isnot well understood.

A possible mechanism for N-cadherin-mediated plas-ticity is suggested by experiments showing that the cy-toplasmic tail of N-cadherin is cleaved sequentially byADAM10 and the �-secretase activity of PS1 in responseto N-methyl-D-aspartate receptor (NMDA) stimulation,and that the released cytoplasmic fragment localizes tothe nucleus where it may function to alter gene tran-scription necessary for LTP (Uemura et al. 2006a,b). Thejuxta-membrane domain of N-cadherin has also beenshown to be important in regulating voltage-gated cal-cium currents in chick ciliary neurons (Piccoli et al.

2004), although the mechanism is unknown. Most re-cently, evidence for N-cadherin function in short-termplasticity in glutamatergic neurons was reported (Jun-gling et al. 2006).

In summary, classical cadherins play key morphoge-netic roles in diverse tissues throughout development bymediating cell interactions necessary for cell sorting, co-ordinated cell movements, planar cell division, and for-mation and maintenance of boundaries in tissues. Stud-ies performed mostly in tissue culture cells have shownthat cadherin expression is regulated at the transcrip-tional level, and at the cell surface through complex anddynamic interactions with the actin cytoskeleton andsignaling pathways. Although studies in vivo indicatethat these control points are also important in morecomplex cellular contexts, further work is required toestablish the significance of these regulatory pathwaysfor cadherin function in tissue morphogenesis.

Protocadherins

Protocadherins are a class of cadherins that are primarilyexpressed in the nervous system, but have additional im-portant developmental expression patterns in nonneuro-nal tissues (Sano et al. 1993). With >60 members identi-fied to date, they make up the largest subfamily of cad-herins (Wu and Maniatis 1999). Interestingly, they arepresent in vertebrates and certain sea sponges with epi-thelial structures, but homologs have not been found inDrosophila or Caenorhabditis elegans (Nichols et al.2006). Work on understanding protocadherin functionsis still in its infancy compared with classical cadherins,but there is tantalizing evidence of roles in tissue devel-opment and a variety of cell functions.

Structural organization of protocadherins

Protein structure Like classical cadherins, protocadher-ins are type I transmembrane proteins. However, theirextracellular domain has six to seven EC repeats thatlack the conserved sequence elements present in classi-cal cadherins (Fig. 1; Junghans et al. 2005). In general,protocadherins have weak adhesive properties in cell ag-gregation assays, and it is unclear whether they mediatehomophilic or heterophilic adhesions (Chen and Gum-biner 2006). In addition, the cytoplasmic domain of pro-tocadherins is structurally diverse, in contrast to the ho-mology between classical cadherins, and less is knownabout cytoplasmic binding partners (see Fig. 4; see be-low). It is likely that the majority of protocadherin in-tracellular domains have the capacity for novel interac-tions and functions that are just beginning to be eluci-dated.

Gene structure The majority of protocadherins can beclassified into three clusters (Pcdh-�, Pcdh-�, and Pcdh-�) each with unique gene structures that encode constantand variable domains. Each of the �-protocadherin and�-protocadherin clusters consists of three constant exons






coding for a portion of the cytoplasmic domain of theentire group preceded by a tandem array of individualvariable exons encoding the rest of the cytoplasmic do-main and the extracellular and transmembrane domainsof each protocadherin; �-protocadherins do not have con-stant exons, but are transcribed from a cluster of singleexon genes (Wu and Maniatis 1999). The similarity be-tween protocadherin and immunoglobulin gene struc-ture raised the possibility that clustered protocadherinsundergo DNA rearrangements similar to that of immu-noglobulin genes (Wu and Maniatis 1999). However, thisdoes not appear to be the case. Instead, expression ofeach protocadherin variable exon is controlled by its ownpromoter (Wu et al. 2001), some of which can be acti-vated by a cleaved cytoplasmic fragment of the cognateprotein (Fig. 3). This may represent a positive feedbackmechanism to reinforce expression of specific protocad-herins within individual cells (Hambsch et al. 2005).There are also multiple splice variants of individual tran-scripts, indicating the potential for great protein diver-sity (Sano et al. 1993; Sugino et al. 2000). Additionalunclustered protocadherins have been identified includ-ing paraxial protocadherin (PAPC), axial protocadherin(AXPC) (Yamamoto et al. 1998; Kuroda et al. 2002), andneural fold protocadherin (NFPC) (Bradley et al. 1998) inXenopus, and �-protocadherins in vertebrates (Redies etal. 2005; Vanhalst et al. 2005).

Protocadherin function in cell organizationin development

Protocadherins in development Functions of protocad-herins have been examined in a variety of developmentalsystems. During Xenopus gastrulation, PAPC is neces-sary for separation of ectoderm and mesoderm, and thisrequires interaction of PAPC with Frizzled-7 and induc-tion of downstream GTPase signaling through the PAPCintracellular domain (Medina et al. 2004; Unterseher etal. 2004). PAPC is expressed in a complementary patternto AXPC, and this pattern is important for boundary for-mation and sorting of cells into the paraxial (PAPC) andaxial (AXPC) mesoderm that form the somites and no-tochord, respectively (Yamamoto et al. 1998; Kuroda etal. 2002). Cell sorting appears to require the extracellulardomain of both proteins and involves regulation of con-vergence and extension movements (Kim et al. 1998).However, PAPC does not mediate cell–cell adhesion di-rectly, but seems to function in cell sorting by modulat-ing C-cadherin adhesion through an unknown mecha-nism (Chen and Gumbiner 2006). The conservation ofthese mechanisms in mammals is not currently estab-lished, as the putative mammalian PAPC homolog,Pcdh8, while expressed in the primitive streak, paraxialmesoderm, somites, and CNS, does not have a loss-of-function phenotype (Yamamoto et al. 2000). However,Pcdh8 may not represent the true PAPC homolog, assequence identity is relatively low (41%) (Frank and Ke-mler 2002).

Other protocadherins have roles in development andtissue morphogenesis. Protocadherin-10 (Pcdh10 or OL-

protocadherin), although primarily expressed in the ner-vous system, is also present in somites and facilitatestheir segregation (Hirano et al. 1999; Murakami et al.2006). NFPC is expressed in ectodermal cells of the neu-ral fold in Xenopus (Bradley et al. 1998) and disruption ofNFPC inhibits neural tube closure and results in disor-ganization of epithelial cells within the folds (Rashid etal. 2006). NFPC also mediates adhesion within the ecto-derm, and expression of dominant negative NFPC causesblistering that can be rescued with C-cadherin, but notN-cadherin or E-cadherin (Bradley et al. 1998). This maybe due to differential adhesive properties of the rescueconstructs or loss of a specific signaling function ofNFPC.

While the importance of protocadherin function ingastrulation and somitogenesis has been shown, theirexpression in the nervous system in combination withtheir diversity and unusual gene structure has led tospeculation that protocadherins are involved in wiring ofneuronal circuitry; that is, each individual neuronal cir-cuit, or set of functionally connected neurons, possessesa fingerprint of protocadherins that in addition to distin-guishing it from every other circuit is required to initiatethe appropriate connections within the developing ner-vous system. At present, evidence supporting this idea ismixed. On the positive side, protocadherins are presentduring embryogenesis and gradually become enriched atsynapses (Kohmura et al. 1998), and the expression ofPcdh-� genes decreases after neurons mature and be-come myelinated (Morishita et al. 2004). Also, Pcdh-�and Pcdh-� localize to the post-synaptic density and havebeen reported to interact with each other (Murata et al.2004). Most significantly, in the mouse olfactory bulband cerebellum, different neurons express different setsof Pcdh-� (Kohmura et al. 1998) and Pcdh-� isoforms(Wang et al. 2002a), respectively. On the negative side,even though multiple Pcdh-� transcripts are expressedby individual Purkinje neurons and their expression isconsistently monoallelic (Esumi et al. 2005), there is noobvious correlation between protocadherin expressionand neuronal function (Frank and Kemler 2002). Further-more, deletion of the entire cluster of Pcdh-� genes inmice resulted in no general defects in neuronal survival,migration, or pathfinding, although there was loss ofsome spinal interneurons due to apoptosis, and spinalsynaptic density was reduced (Wang et al. 2002b). Thelack of general effects of Pcdh-� deficiency on the ner-vous system might be due to compensation by Pcdh-�and/or Pcdh-� proteins. However, the localized effects ofdeletion of Pcdh-� on interneurons of the spinal cord alsoindicate that expression of different members of the pro-tocadherin family might specify both the survival andsynaptic organization of different neuronal populations.

Protocadherin function in cell signaling Although pro-tocadherin expression within the nervous system is wellestablished, the molecular mechanism underlying theirfunction is not currently known. The majority of pro-tocadherins exhibit weak homophilic adhesion in aggre-gation assays (Chen and Gumbiner 2006). However, pro-

Halbleib and Nelson





tocadherin cell–cell adhesion can be strengthened if thecytoplasmic tail is replaced with that of E-cadherin(Obata et al. 1995), suggesting that the extracellular do-main of protocadherins is able to form trans interactions,but the cytoplasmic domain does not efficiently stabilizethose interactions to facilitate adhesion. Instead, the pri-mary function of protocadherins may be to relay a signalto the cytoplasm in response to cell recognition, and notto maintain physical interactions between cells (Frankand Kemler 2002).

Protocadherins interact with a variety of proteins thatcould propagate intracellular signals. Pcdh-� proteins inmice have a RGD motif that can facilitate interactionswith integrins in vitro (Fig. 2; Mutoh et al. 2004). Pcdh-�isoforms also interact with neurofilaments and the ac-tin-bundling protein Fascin, depending on which con-stant exon codes for their intracellular domain (Triana-Baltzer and Blank 2006); the cytoplasmic protein Fyn,which has been implicated in higher brain functionssuch as LTP, memory, and spatial learning (Kohmura etal. 1998); and receptors for Reelin, which is involved incortical organization and may act with Pcdh-�s to ter-minate neuroblast migration (Senzaki et al. 1999). Taf1,which functions in chromatin remodeling, interactswith NFPC and loss of Taf1 phenocopies knockdown ofNFPC (Heggem and Bradley 2003), raising the possibilitythat NFPC engagement may alter gene transcription. Fi-nally, protocadherin functions can be mediated by pro-teolysis. Pcdh-� proteins are cleaved specifically and se-quentially by ADAM10 and PS1 (Marambaud et al. 2002;Haas et al. 2005). In addition to modulating adhesion(Reiss et al. 2006), proteolysis of Pcdh-� generates a cy-toplasmic fragment that localizes to the nucleus and ac-tivates transcription of Pcdh-� genes (Fig. 3; Hambsch etal. 2005). However, it appears to activate the promoter ofevery isoform, so specificity at the level of individualcells must be generated by another mechanism.

In summary, protocadherins play critical roles duringembryogenesis, particularly within the CNS. It is clearthat these functions frequently require activation of in-tracellular signaling in response to engagement of cell–cell interactions. In combination with their potential forgreat protein diversity, this differential signaling capabil-ity suggests a powerful mechanism for highly specificresponses to the initiation of cell–cell adhesion, but elu-cidation of the molecular details will require furtherstudy.

Atypical cadherins and PCP

PCP refers to polarized orientation of epithelial cellsalong the axis of the cell monolayer. This level of tissueorganization was originally characterized in Drosophilain screens for mutants that affected the polarity of winghairs, leg bristles, and photoreceptor omatidia (Fanto andMcNeill 2004). Recent studies of PCP in vertebrates sug-gest that during development conserved components ofthis pathway coordinate global spatial cues with cellmovement and orientation to achieve appropriate tissuemorphogenesis. A core component of the signaling path-

way that sets up PCP is the seven-membrane-spanningreceptor frizzled (Fz) (Klein and Mlodzik 2005). Fz is lo-calized asymmetrically in cells (Fig. 4D), and it is nowclear that atypical members of the cadherin family playcritical roles in regulating Fz localization and hence PCPsignaling.

Structure and interactions of atypical cadherins

The large, atypical cadherins Dachsous (Ds), Fat, and Fla-mingo (Fmi) are involved in PCP signaling (Fig. 4D). In-stead of five extracellular ECs characteristic of classicalcadherins, Ds and Fat have 27 and 34 ECs, respectively(Mahoney et al. 1991; Clark et al. 1995). Fmi is uniqueamongst the cadherins, as it is the only member with aseven-pass, rather than a single, transmembrane domainand has a large extracellular sequence that includes nineECs (Fig. 1; Nakayama et al. 1998). The cytoplasmic do-mains of Ds and Fat have sequence homology with the�-catenin-binding site of classical cadherins (Mahoney etal. 1991; Clark et al. 1995), although there is no evidencethat either binds �-catenin; in mammalian tissue culturecells, Fat and the classical cadherin–catenin complexhave nonoverlapping distributions (Tanoue and Takeichi2004). Instead, mammalian Fat1 binds to Ena/VASP, afamily of proteins that regulate actin cytoskeleton as-sembly and dynamics (Fig. 2; Moeller et al. 2004; Tanoueand Takeichi 2004).

Fmi, Ds, and Fat interact at several structural andfunctional levels. In Drosophila, Fmi functions down-stream from Fz (Fig. 4D). Its expression precedes mor-phological changes associated with PCP, and Fmi local-izes asymmetrically within those tissues (Usui et al.1999). Although Fmi homophilic adhesion has beendemonstrated in vitro, its role in PCP appears to be in-dependent of this property (Lu et al. 1999).

Ds, which acts upstream of Fz (Yang et al. 2002), isexpressed in a gradient across certain Drosophila tissues,but Ds expression across the entire epithelium of thewing but not the eye can rescue loss-of-function PCPdefects, indicating that a gradient of Ds is not alwaysnecessary for PCP (Simon 2004). Ds has been implicatedin cell proliferation as well as border formation in theDrosophila wing disc (Clark et al. 1995; Rodriguez 2004).Ds binds Fat directly and negatively regulates its activity(Yang et al. 2002; Matakatsu and Blair 2004), and theextracellular domain of Ds is sufficient for its function inPCP, indicating that it may act as a ligand during PCPsignaling (Fig. 2; Matakatsu and Blair 2006).

Loss of Fat function leads to hyperproliferation of Dro-sophila imaginal discs (Mahoney et al. 1991). Fat regu-lates PCP at least in part by binding the transcriptionalcorepressor Atrophin (Fig. 2; Fanto et al. 2003). Intri-guingly, it was recently shown that only the cytoplasmictail of Fat is required for its effects on tissue growth andPCP (Matakatsu and Blair 2006). These results indicatecomplex interactions between the atypical cadherins inPCP, involving some homophilic and heterophilic bind-ing and regulation of signaling cascades. Therefore, itappears that Ds, Fat, and Fmi mediate cell–cell interac-






tions in PCP that propagate polarity cues and regulatetissue size, and are not just responsible for mechanicaladhesion between cells.

Atypical cadherins in vertebrate development

The characterization of PCP protein homologs in verte-brates has recently begun. Specific homologs of cadher-ins involved in PCP are expressed very early in verte-brate development at the primitive streak stage and arepresent primarily in epithelia and CNS, with some ex-pression within endothelia and smooth muscle (Dunneet al. 1995; Hadjantonakis et al. 1998; Nakayama et al.1998; Cox et al. 2000). In vertebrate development, PCPcomponents function in convergence and extensionmovements. Fmi mediates extension during Zebrafishgastrulation (Formstone and Mason 2005a). Fmi is up-regulated in the chick neural epithelium immediatelyprior to neural tube closure (Formstone and Mason2005b), a morphological event that has been shown to beregulated by other vertebrate PCP components (Goto andKeller 2002; Hikasa et al. 2002; Wallingford and Harland2002). Knockdown of Fat1 increases cell proliferation invertebrates (Hou et al. 2006). In addition, mice with mu-tant Atrophin-2 have embryonic patterning defects(Zoltewicz et al. 2004). Atrophin-1 mutations are linkedto neurodegenerative disease, which appears to correlatewith its nuclear localization (Nucifora et al. 2003). AsAtrophin binds Fat in invertebrates, this suggests thatFat, as well as other PCP components, may also functionin these processes. In the CNS, the vertebrate Fmi ortho-log, Celsr3, is required for the formation of axonal tracts(Tissir et al. 2005).

Another form of PCP in vertebrates is the organizationof hair cell stereocilia within the inner ear. The mouseFmi ortholog Celsr1 localizes asymmetrically along thetissue plane in chick hair cells (Davies et al. 2005), andmutant Celsr1 disrupts stereocilia architecture (Curtinet al. 2003). Interestingly, both protocadherin-15(Pcdh15) and Cadherin-23 are mutated in the Usher Isyndrome, a hereditary condition causing both deafnessand vision loss (El-Amraoui and Petit 2005). Pcdh15 hasbeen identified as the tip-link antigen, which localizes tothe distal end of sensory hair bundles and could functionto gate the hair cell mechanotransducer channel (Ahmedet al. 2006). Cadherin-23 is expressed in developing hairbundles at centrosomes and along the stereocilia, and isrequired for mechanotransduction (Siemens et al. 2004;Sollner et al. 2004; Lagziel et al. 2005), but its function isnot yet clear. A Drosophila ortholog of Pcdh15, Cad99C,regulates the length of apical microvilli in ovarian fol-licle cells (D’Alterio et al. 2005). These studies highlightroles for a variety of cadherin subtypes in the complexorganization of stereocilia, and it will be interesting tolearn how their activities are coordinated and function inintercellular pathways.

The involvement of atypical cadherins in PCP illus-trates the diverse morphological roles of the cadherinfamily. While facilitating cell–cell interaction throughadhesion is an important cadherin function, they also

have broader roles in cell recognition throughout tissuesand participate in a complex, highly conserved signalingcascade. Atypical cadherins act to maintain polarityacross tissues, regulate their size by controlling prolif-eration, and coordinate major morphogenetic move-ments in development.

Conclusions

Although cadherins almost certainly originated as ameans of mechanical cell–cell adhesion, their activitieshave been co-opted into all aspects of tissue morphogen-esis. Atypical cadherin homologs, but not classical cad-herins, have recently been identified in the sponge O.carmela, which has a simple body plan and only epithe-lial tissue structures (Nichols et al. 2006). This, coupledwith the expansion of the cadherin family in higher or-ganisms, supports the idea that cadherins initially medi-ated cell–cell adhesion in simple organisms, but subse-quently their roles diversified, in parallel with increasesin their number and structural variation, to morphoge-netic processes required in more complex organisms.

Cadherin expression is controlled by a variety of regu-latory mechanisms at the level of gene transcription andprotein trafficking and organization at the cell surface.This allows for precise, and in some cases rapid, modu-lation of cadherin functional activity in response to de-velopmental cues. The diverse roles of cadherins are fa-cilitated by their interactions with a wide range of cyto-plasmic proteins, including cytoskeletal regulators,protein kinases and phosphatases, and transcriptionalcofactors. Classical cadherins function in cell sorting viatheir differential adhesive strengths, and provide strongcell–cell adhesion to maintain the structural and func-tional integrity of tissues. While protocadherin-mediatedcell–cell adhesion appears rather weak, it is likely thatthey initiate specific intracellular signaling in responseto extracellular interactions; these downstream effectsmay be key to the development of the CNS. Atypicalcadherins act within a pathway of conserved PCP com-ponents to detect and maintain polarity across tissues.

Thus, the cadherin family not only plays importantroles based on their primary function in the formation ofcell–cell adhesions, but has also evolved to specify cell–cell recognition and sorting, boundary formation in tis-sues, coordination of multicell movements, and the es-tablishment and maintenance of cell and tissue polarity.In the future, it will be important to determine how cad-herin interactions that have been established in vitrotranslate to functions within tissues. In particular, thesignificance of heterophilic versus homophilic cadherinbinding, the nature and regulation of linkages to thecytoskeleton, and modulation by and of signaling cas-cades are key questions.

Acknowledgments

We thank Adam Kwiatkowski and Lene Nejsum for commentson the manuscript. Work from the Nelson laboratory is sup-ported by the NIH (GM35527), and a HHMI predoctoral Fellow-ship (to J.M.H).

Halbleib and Nelson





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