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doi: 10.1242/10.1242/jcs.00167

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Nectin and afadin: novel organizers of intercellular junctions

Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan

View larger version (25K): [in a new window]   Fig. 1. Homotypic, interneuronal and heterotypic junctions. (A) The junctional complex in small intestine absorptive epithelial cells. The junctional complex, which consists of AJs, TJs and DSs, localizes at the most apical region of the lateral membrane. These junctional structures are typically aligned from the apical to basal sides. (B) Synapses. Synapses are intercellular junctions that are typically formed between axons and dendrites of neurons. There are morphologically various types of synapses. (C) Two types of intercellular junctions and spermatogenesis. The seminiferous epithelium of the testis has Sertoli-cell—Sertoli-cell and Sertoli-cell—spermatid junctions. At Sertoli-cell—spermatid junctions, the F-actin bundles surround the spermatid heads like parallel rings (3D view). Unlike this figure, one Sertoli cell does not bind the germ cells of all developmental stages at the same time. The germ cells in the epithelium are locally synchronized for their development. The dashed boxes in A, B and C correspond to the panels in Fig. 4A, B and C, respectively.

View larger version (13K): [in a new window]   Fig. 2. Molecular structures of nectin and afadin. TM, transmembrane region.

View larger version (23K): [in a new window]   Fig. 3. Models for the intercellular adhesion activities of cadherin and nectin. (A) Cadherin. (B) Nectin.

View larger version (31K): [in a new window]   Fig. 4. Molecular basis of homotypic, interneuronal and heterotypic junctions. (A) AJs and TJs. At AJs, E-cadherin serves as an essential CAM. The cytoplasmic region binds ß-catenin, which in turn binds -catenin. -Catenin is associated with the circumferential F-actin bundles directly and indirectly through vinculin and -actinin. Nectin also functions as a CAM at AJs, but is more highly concentrated at AJs than E-cadherin. The cytoplasmic region binds afadin that is directly associated with the F-actin bundles. Afadin and -catenin are associated with each other presumably through an unidentified molecule `X'. At TJs, claudin and JAM function as CAMs. Occludin is another transmembrane protein at TJs. The cytoplasmic regions of claudin, JAM and occludin bind ZO-1, ZO-2 and ZO-3. ZO-1 and ZO-2 are directly associated with F-actin and form a dimer with ZO-3. Afadin and ZO-1 may be associated with each other through an unidentified molecule `Y'. F-Actin and peripheral membrane proteins shown in the right-side cell are omitted in the left-side cell. (B) Synapses. At the synapses between mossy fiber terminals and pyramidal cell dendrites in the CA3 area of hippocampus, both synaptic junctions and puncta adherentia junctions are highly developed. At the puncta adherentia junctions, nectin-1 and nectin-3 localize asymmetrically at the presynaptic and postsynaptic sides, respectively. Afadin, N-cadherin and catenins localize symmetrically at the both sides. Synaptic junctions are associated with presynaptic active zones where synaptic vesicles, Ca2+ channels and many other components, such as bassoon, localize and with PSDs where neurotransmitter receptors localize. F-Actin shown in the postsynaptic side is omitted in the presynaptic side. (C) Sertoli-cell—spermatid junctions. Nectin-2 in Sertoli cells and nectin-3 at spermatids form a hetero-trans-dimer at Sertoli-cell—spermatid junctions. The F-actin bundles surround the spermatid heads like parallel rings (3D view). The nectin-based adhesive membrane microdomains show one-to-one linkage with each F-actin bundle. ES contains not only F-actin bundles but also a flattened cistern that is connected to microtubules.

View larger version (23K): [in a new window]   Fig. 5. A model for the role and mode of action of nectin in the formation of a junctional complex in epithelial cells. (A) Formation of AJs. When the two migrating cells contact through their protrusions, nectin and E-cadherin separately form trans-dimers that form microclusters at intercellular contact sites. The nectin-based microclusters are mainly formed at the initial stage. The nectin-based microclusters then recruit E-cadherin, which results in the formation of a mixture of nectin- and E-cadherin-based microclusters (primordial spot-like junctions). These primordial junctions fuse to form short line-like junctions, which develop into more matured AJs. Upper panel, transverse section view; lower panel, cross-section view. (B) Formation of TJs. During the formation of AJs, JAM is first assembled at the apical side, followed by the recruitment of claudin, which eventually leads to the establishment of TJs (cross-section view).