Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Cadherin superfamily genes: functions, genomic organization, and neurologic diversity Takeshi Yagi1,3 and Masatoshi Takeichi2 1Laboratory of Neurobiology and Behavioral Genetics, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan; 2Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan To answer the question of how the highly sophisticated the molecular events underlying the establishment of functions of the central nervous system (CNS) are born, complex and organized networks of neuronal connec- we need to gain insight into the molecular mechanisms tions in the CNS, which may provide further insight into that generate an enormous number of diversified neu- the processes giving rise to diverged brain functions in rons and their specific interactions. The complex and various species and individuals, as well as the molecular highly organized neural networks in the CNS ultimately basis of psychociatic diseases. generate brain function, including innate and acquired behavior. Interestingly, the CNS is in part similar to the immune system, both are produced as complex, diversi- Cadherin superfamily: general molecular features fied, and well-organized networks from limited genomic At least 80 members of the cadherin superfamily have information. The immune system promotes the recogni- been shown to be expressed within a single mammalian tion of the enormous battery of foreign antigens through species; these members include classic cadherins, des- the random diversification of T-cell receptors (TCR) and mogleins, desmocollins, protocadherins, CNRs, Fats, B-cell receptors (BCR) of the immunoglobulin superfam- seven-pass transmembrane cadherins, and Ret tyrosine ily by germ line rearrangement and/or somatic muta- kinase (Fig. 1). All members of the cadherin superfamily tion. Analogous regulatory processes are not known for are transmembrane proteins, with some exceptions, and the CNS. However, recent studies of the cadherin super- are characterized by a unique domain, called cadherin family have provided valuable insights into the genera- motif or EC domain, containing the negatively charged tion of diversified and organized networks in the CNS. DXD, DRE, and DXNDNAPXF sequence motifs, which A large number of cadherin superfamily genes have are involved in Ca2+ binding (Takeichi 1990). The EC been identified to date, and most of them seem to be domains are tandemly repeated in the extracellular seg- expressed in the CNS. In particular, primary cadherins ment of all of the cadherin superfamily molecules, and (classic cadherins) were identified as synaptic compo- the number of the EC domains varies considerably with nents, and roles for them in neuronal circuitry, synaptic the members. Although the presence of the EC domains junction formation, and synaptic plasticity have been is the hallmark of this molecular family, the amino acid suggested (Suzuki et al. 1997; Tang et al. 1998; Honjo et sequences of other parts, in particular, the cytoplasmic al. 2000; Manabe et al. 2000; Tanaka et al. 2000). In ad- domain, significantly diverge among the members, sug- dition, the expression of a novel cadherin, Arcadlin, was gesting that their functional diversification has occurred found to be up-regulated during activity-dependent syn- during evolution. In Drosophila, six cadherin superfam- aptic plasticity (Yamagata et al. 1999). Moreover, a sub- ily members have thus far been identified, and the Cae- family of the cadherin superfamily, CNR (cadherin-re- norhabditis elegans genome database indicates that this lated neuronal receptor) proteins bound to tyrosine ki- species has ∼20 genes of this superfamily. Interestingly, nase Fyn, is localized in synaptic membrane (Kohmura et only 1 molecule, of the 20 C. elegans cadherins, was al. 1998). At least three protocadherin gene subfamilies identified as the classic cadherin type. including the CNRs are derived from an unusual geno- mic organization similar to that of BCR and TCR gene clusters (Wu and Maniatis 1999; Sugino et al. 2000). Classic cadherins and Fats These findings have interesting implications regarding The structure and function of classic and desmosomal cadherin subfamilies have been reviewed repeatedly 3Corresponding author. (e.g., Provost and Rimm 1999; Steinberg and McNutt E-MAIL [email protected]; FAX 81-564-55-7741. 1999; Troyanovsky 1999; Gumbiner 2000), and only a GENES & DEVELOPMENT 14:1169–1180 © 2000 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/00 $5.00; www.genesdev.org 1169 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Yagi and Takeichi Figure 1. Schematic diagram of the molecular structure of the cadherin superfamily (blue) and their cytoplasmic interactors (yellow, pink). Classic cadherins have been primarily isolated as Ca2+-dependent cell adhesion molecules. Activity of cell adhesion is regulated by catenins bound to its cytoplasmic region. Approximately 80 members of the cadherin superfamily have been isolated. Most members are expressed in the CNS. CNRs bind to Fyn-tyrosine kinase in their cytoplasmic region. Interestingly, Drosophila cadherins have many EC repeats. The number of extracellular tandem repeats, ECs, varies. brief summary of their properties is described here. that of vertebrate classic cadherins (Tepass 1999). DE- These are homophilic adhesion molecules, and for their cadherin is expressed predominantly in epithelial tis- homophilic interactions, the EC domains play a crucial sues, and DE-cadherin mutations impair dynamic cell role. The intracellular domains are conserved among the arrangement and rearrangement during oogenesis and members of each subfamily, and in the case of classic embryogenesis. DN-cadherin mutations result in either cadherins, they interact with catenin p120ctn and embryonic lethality or uncoordinated locomotion in ␤-catenin at different portions of the cytoplasmic do- adults, and mutant embryos exhibit failures in axon pat- main. The latter binds to ␣-catenin, and this molecular terning, including position shifts, defective bundling, complex further associates with vinculin and other cy- and errors in directional migration of growth cones. toskeletal proteins, resulting in the organization of ad- Fat and Dachsous organize another subfamlily, both herens junction, or zonula adherens in polarized epithe- contain large tandem arrays of EC domains (Fig. 1). Re- lial cells. cessive lethal mutations in the ft (fat) gene cause hyper- Related molecules have been identified in inverte- plastic, tumor-like overgrowth of larval imaginal discs in brates. However, the structural organization of verte- a cell-autonomous fashion, defects in differentiation and brate classic cadherins is not entirely conserved in the morphogenesis, and death during the pupal stage (Bryant invertebrate species (Oda and Tsukita 1999). For ex- et al. 1988; Mahoney et al. 1991). Mutations in the ample, although Drosophila DE- and DN-cadherins are dachsous gene lead to defects in the morphogenesis of similar to vertebrate classic cadherins in respect to their the thorax, legs, and wings during development of imagi- binding ability to ␤-catenin (Armadillo) at the cytoplas- nal discs (Clark et al. 1995). However, molecular mecha- mic domain, their extracellular domains are consider- nisms underlying these phenotypes are poorly under- ably divergent. Drosophila cadherins have more EC do- stood. mains than the vertebrate cadherins, and also have an insertion of distinctive sequences between the last EC Seven-pass transmembrane cadherins and transmembrane domains, which include a cysteine- rich segment, and a laminin A-like domain (Iwai et al. Recently, an unusual class of cadherins with a seven- 1997). Despite such differences, their function as homo- pass transmembrane domain, which have similarity to a philic adhesion molecules appears to be homologous to group of peptide hormone-binding, G-protein-coupled re- 1170 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Cadhedrin superfamily ceptors have been identified in both vertebrates and in- expressed (Sano et al. 1993). Chimeric molecules con- vertebrates. One of these cadherins, Drosophila Fla- taining the extracellular domains of Pc2 and Pc3 fused to mingo (Fmi), is located at cell–cell boundaries in a polar- the cytoplasmic domain of E-cadherin display stronger ized fashion, and functions together with Frizzled (Fz) for homophilic cell adhesion activities than the original the acquisition of proximal-distal polarity of wing hair ones. These results indicate that the EC domains of pro- cells. Mutants lacking Fmi exhibit disorganized planer tocadherins can undergo homophilic interactions, as polarity, and the polarized distribution of Fmi is influ- found for those of classic cadherins, but the functions of enced by alternating patterns of Fz expression (Usui et al. the cytoplasmic domain are not identical between these 1999). Such actions of Fmi are likely mediated by a cy- two subfamilies. Molecules associated with the cyto- toplasmic signaling cascade distinct from that for classic plasmic region of Pc2 and Pc3 are yet to be found. An- cadherins. It is noteworthy that members of the secretin other member of the protocadherin group, Arcadlin, also receptor