Breaking through the tight junction barrier.

Abstract

T H~ tight junction, or zonula occludens, is an organeile of crucial importance to the development and function of most organ systems in vertebrates because it enables epithelia and endothelia to create eompositionaily distinct fluid compartments. The tight junction forms a continuous permeability barrier between adjacent cells that regulates the flux of molecules through the paracellular space (2). It also creates a boundary in the plasma membrane bilayer that separates the cell surface into biochemicaily and functionally distinct apical and basolateral membrane domains, enabling the cells to carry out polarized transport (8). The tight junction is a fascinating structure. It forms the closest contact between adjacent cells known in nature, so close, in fact, that it was once believed to be a fusion between outer leaflets on the adjacent bilayers (11, 23). We now know that it does not make an absolute seal, but instead contains discrete ion selective pores through the extracellular portion of the junction (Fig. 1). The permeability properties of the tight junction are quite variable in different epithelia, depending on the specific physiological requirements for transepitheliai (or transendothelial) solute transport (6). Moreover, tight junction permeability can be regulated physiologically within a given e_pithelium (13). Thus, the extracellular portion of the tight junction has to accomplish two main tasks; to form extremely narrow intercellular adhesions ~that occlude a region of extracellular space, and to create regulatable pores for selective molecular sieving. The tight junction also has characteristics of a biological polymer. By freeze-fracture electron microscopy, which reveals intramembrane structure, the tight junction appears as a set of long, parallel, linear fibrils that circumscribe the cell, with short fibril fragments interconnecting the main parallel array (19). The assembly of these fibrils seems to be regulated in a way that is crucial to tight junction physiology. Various epithelial cell types differ in their number of parallel fibrils, and generally, a greater number of fibrils correlates with decreased junctional permeability (5, 15). Fibril assembly also seems to be quite dynamic in some cell types (Fig. 2). In the most impressive examples, a rapid, massive stimulation of fibril assembly occurs when epithelial cells are exposed to certain noxious stimuli (10, 20). More subtle alterations in fibril number also occur during less dramatic instances of junctional regulation (7, 12). Rapid fragmentation of the fibrils is also observed, for example, when leukocytes migrate across epithelia or when intestinal junctions