Junctional barrier complexes undergo major alterations during the plasma membrane transformation of uterine epithelial cells

Human Reproduction, Vol. 15, (Suppl. 3), pp. 182-188, 2000 Junctional barrier complexes undergo major alterations during the plasma membrane transformation of uterine epithelial cells Christopher R.Murphy Department of Anatomy and Histology, The University of Sydney, NSW, Australia Address for correspondence: Department of Anatomy and Histology, The University of Sydney, NSW 2006, Australia. E-mail: Junctions in the plasma membrane of uterine epithelial cells as well as between these cells and their extracellular environment are examined in this review to see if a synthetic appreciation of their role can be gained from the disparate evidence presently available. Major changes in most junctional components are noted during early pregnancy and the role of progesterone and oestrogen in promoting these changes is examined. In particular it is noted that while tight junctions become deeper and morphologically 'tighter' towards the time of implantation, other basolateral junctional structures as well as their cytoskeletal associations are absent. These junctional alterations are part of the 'plasma membrane transformation' of early pregnancy and allow the conclusion that while paracellular permeability is reduced by the time of blastocyst attachment, the epithelial cells are paradoxically less firmly attached to each other, and to their extracellular environment. Key words: barrier function/epithelial cell/junction/ pregnancy/uterus Introduction Epithelial cells have special structural features and among these are the junctions they form with each other and with their extracellular environment. These junctions contribute in various ways to the barrier function of epithelia — the capacity of this tissue to separate different environments. The 182 uterine epithelium has the usual complement of junctional types but, unlike other epithelia, this epithelium has roles and sensitivities not shared by these other epithelia. Unique among epithelia, the uterine epithelium is cyclically altered by ovarian hormones which regulate its capacity to permit blastocyst implantation, and it is then periodically invaded from its apical surface by the implanting blastocyst. The uterine epithelium thus has, in addition to the usual epithelial barrier function, the function of regulating the early events of uterine receptivity for implantation. The effects of the ovarian hormones on the uterine epithelium are many but those on the plasma membrane have been described as 'the plasma membrane transformation' (Murphy, 1993, 1995, 1998; Murphy and Shaw, 1994) to encapsulate the concept of a process of change involving all membrane domains during early pregnancy. The epithelial cell junctions are key players in epithelial events during early pregnancy and reports on different junctional components have been available for some years. Recently, however, new data on cytoskeletal and molecular components of the junctions of uterine epithelial cells have highlighted the extent of junctional involvement in the processes of change during early pregnancy in particular. This review draws together our knowledge of junctional processes in uterine epithelial cells and highlights the inter-relatedness of junctional involvement in the plasma membrane transformation of early pregnancy and uterine function more generally. © European Society of Human Reproduction & Embryology Junctions of uterine epithelial cells The tight junction (zonula occludens) The lateral plasma membranes of epithelial cells face the relatively constant environment of another epithelial cell and thus — unlike the apical and basal portions of a plasma membrane which face different external and internal environments respectively — are generally similar to each other. This is also true of the uterine epithelium, notwithstanding the reproductive specialization of these epithelial cells. The tight junction is the most apical in the junctional complex and was originally described in a thin-section electron microscopic study of several epithelia (Farquhar and Palade, 1963); these workers used the term zonulae occludentes (occluding junctions) and surmised their role in preventing or reducing paracellular movement of molecules. Because of its capacity to expose laterally extended regions of plasma membrane, freezefracture is uniquely suited for the study of tight junctions and has been extensively employed to examine the rows of closely packed integral membrane proteins (IMP) which appear as strands in replicas and constitute the freeze-fracture appearance of these junctions (Claude and Goodenough, 1973; Staehelin, 1974; Cereijido, 1992). In uterine epithelial cells, tight junctions were first studied in rat uterine epithelial cells during early pregnancy (Murphy et al., 1982a); it was found that on day 1 these junctions consisted almost entirely of strands running parallel to the apical surface with few vertical strands connecting the horizontally oriented ones. By the time of blastocyst attachment, however, the junctions had become over three times deeper, at up to 3 (im down the lateral plasma membrane, and also much more complex in structure with many interconnections between the strands, which by then consisted of arrays of branching, anastomosing structures. These changes in structure are predominantly under the control of progesterone. Earlier, the capacity of ovarian hormones injected into ovariectomized rats to generate different patterns of tight-junctional organization had been studied (Murphy et al., 1981) and it was found that oestrogen produced a tight junction consisting largely of the parallel strand type whereas progesterone alone resulted in the much more complex pattern of many intercon- nections and a greater depth down the lateral membrane. Progesterone and oestrogen together produced effects not discernibly different from progesterone alone. An increase in depth and geometrical complexity of tight junctions has similarly been described during early pregnancy in rabbits together with the formation of isolated strands of macular tight junctions below the main complex (Winterhager and Kuhnel, 1982); an increase in complexity but not depth around the time of implantation in pigs was also interpreted as having been progesteroneinduced (Johnson et al., 1988). In women, tight junctions are geometrically more complex earlier than later in the menstrual cycle (Murphy et al., 1982b, 1992). It is thus remarkable that in all the species where sufficient evidence exists, it points to a progesterone-induced increase in tightjunctional complexity. Tight junctions are well known as regulators of paracellular flow with more strands and particularly a more complex geometry, generally indicating decreased paracellular permeability (Claude and Goodenough, 1973; Gonzalez-Mariscal, 1992). It would seem likely that the increasing complexity and morphological 'tightness' seen during early pregnancy is a reflection of the need to preserve the lu (...truncated)