ABSTRACT
A hallmark in the development of multicellular organisms is the assembly of cellular sheets that separate compartments of different compositions. For example, in the cochlea of the inner ear the perilymph of the scala vestibuli and scala tympani has very different ionic composition as compared to the endolymph of the scala media (1, 2). Maintenance of different compartments is performed by epithelial or endothelial cells, which adhere to each other by forming different types of intercellular junctions (3), including desmosomes (4), adherens junctions (5), gap junctions (6), and tight junctions (7, 8) (Fig. 1A). Epithelial cells execute a variety of vectorial functions in transport and secretion. To accomplish this they are organized in a polarized fashion with structurally and functionally distinct apical and basolateral plasma membrane domains (reviewed in Ref. 9). The movement of solutes, ions, and water through epithelia occurs both across and between individual cells, and is referred to as the transcellular and the paracellular routes, respectively (Fig. 1B). Both routes display cell-specific and tissue-specific variations in permeability, and together account for the distinct transport properties of each tissue. The basis for transcellular transport, through specific membrane pumps and channels that actively generate the unique electroosmotic gradients and secretory fluids characteristic of each epithelium, is well known. In contrast, our understanding of the epithelial paracellular pathway, which is responsible for maintenance of gradients by restricting back diffusion between cells,
and of the mechanisms that establish and maintain epithelial cell polarity, is more limited. The major barrier in the paracellular pathway is created by the tight junction (TJ), also
known as zonula occludens (ZO; “occluding belt”). TJs can be found in various epithelial tissues, in which they form regions of intimate contact between the plasma membranes of adjacent cells (3). In freeze-fracture replicas of epithelial cells prefixed with glutaraldehyde, TJs usually appear either as a continuous band-like network of branching and interconnecting thin ridges on P faces (the cytoplasmic leaflet of plasma membranes), or as a corresponding pattern of grooves on E faces (the extracytoplasmic leaflet of plasma membranes) (10) (Fig. 2). A closer examination of these structures suggested that each of the interconnected lines of attachment of TJ regions consists of two adhering rows, one in each membrane, of closely spaced adhesion particles (11). These particles are proteins that bridge the width of the adjoining membranes and are linked together in the plane of the intercellular space. There is some evidence that TJs form an intramembrane diffusion barrier that restricts the lateral diffusion of apical and basolateral membrane components, thus maintaining cellular polarity (“fence function”) (12-15). TJs also close or seal the space between
cells and thus set up a semipermeable barrier that prevents or reduces paracellular diffusion (“barrier function”) (16). The actual barrier capacity of TJs can be determined by measurements of the electrical resistance across the epithelium (17). Barrier function of TJs was demonstrated for relatively large molecules, such as hemoglobin (3), as well as for smaller molecules, such as the colloidal tracer lanthanum hydroxide (18). TJs partly block the paracellular transport of water and small electrolytes. Depending on the functional requirements of an epithelium, there may be small or large amounts of water and small solutes flowing passively through the TJ (17). The paracellular permeability of different epithelia was found to correlate with the number of TJ strands along the apicalbasal axis (19). The morphological pattern of the strands also varies among tissues; however, the physiological correlate of these ultrastructural differences is yet unknown.
