The molecular organization of tight junctions

I T is seven years since the identification of ZO-1, the first protein localized at tight junctions (TJs) t (60). Two years later, a second TJ-associated protein, cingulin, was characterized (9). More recently, two additional proteins, ZO-2 (26) and 7H6 (68), have been added to the list. All these proteins belong to the cytoplasmic "plaque" domain of TJs, based on morphological and/or biochemical criteria. In epithelial polarized cells TJs (zonulae occludentes) (for reviews see references 23, 56) represent the apical element of a tripartite junctional complex, including the zonula adhaerens and the desmosome (16). In this issue, Tsukitas's group (32) reports the cloning of a 220-kD protein, originally identified at the undercoat of cad-herin-containing cell-cell contact sites, in nonepithelial cells (31) and its characterization as the mouse homologue of ZO-1. The occurrence of ZO-1/220-kD protein in nonepithelial tissues (see also reference 29) casts doubt on its specificity as a T J-exclusive marker and emphasizes the importance of classifying junctions based on their functional properties, composition and morphology. The interaction of ZO-1/220-kD protein with spectrin (31) and its colocalization with cadherins (31, 32) raises new questions about the roles of these proteins in TJ assembly and function. This mini-review will discuss these new perspectives, in the context of past efforts and recent progress in understanding the organization of epithelial TJs. Why are TJs considered one of the most characteristic structural markers of the polarized epithelial phenotype? TJs provide a continuous seal around the apical region of the lateral membranes of adjoining epithelial cells, preventing the free passage of molecules and ions across the "paracellular" pathway , e.g., the extracellular space between the lateral membranes of neighboring cells. This "barrier" function of TJs distinguishes them from other types of junctions, and defines two distinct compartments of the extracellular space, the "luminal" (apical) and the "serosal" (basolateral) compartment , the latter in continuity with the interstitial fluids and, ultimately, the blood. The ability of TJs to act as permeability barrier is shown by using electron dense tracers and measuring fluxes of radiolabeled markers and ions across epithelial monolayers (7, 14). A second function attributed to TJs in epithelia is to separate apical and basolateral plasma membrane domains, which differ in protein and lipid composition and carry out specialized functions (reviewed in reference 54). TJs are thought to represent the "fence; preventing the free diffusion of lipids in the exoplasmic membrane leaflets and the …