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PubMed1984

Cell-cell interactions of isolated and cultured oligodendrocytes: formation of linear occluding junctions and expression of peculiar intramembrane particles.

Oligodendrocytes were isolated from lamb brain. Freshly isolated cells and cultured cells, either 1- to 4-day-old unattached or 1- to 5-week-old attached, were examined by thin section and freeze-fracture electron microscopy. Freeze-fracture of freshly isolated oligodendrocytes showed globular and elongated intramembrane particles similar to those previously described in oligodendrocytes in situ. Enrichment of these particles was seen at sites of inter-oligodendrocyte contact. Numerous gap junctions and scattered linear tight junctional arrays were apparent. Gap junctions were connected to blebs of astrocytic plasma membrane sheared off during isolation, whereas tight junctions were facing extracellular space or blebs of oligodendrocytic plasma membrane. Thin sections of cultured, unattached oligodendrocytes showed rounded cell bodies touching one another at points without forming specialized cell junctions. Cells plated on polylysine-coated aclar dishes attached, emanated numerous, pleomorphic processes, and expressed galactocerebroside and myelin basic protein, characteristic markers for oligodendrocytes. Thin sections showed typical oligodendrocyte ultrastructure but also intermediate filaments not present in unattached cultures. Freeze-fracture showed intramembrane particles similar to but more numerous, and with a different fracture face repartition, than those seen in oligodendrocytes, freshly isolated or in situ. Gap junctions were small and rare. Apposed oligodendrocyte plasma membrane formed linear tight junctions which became more numerous with time in culture. Thus, cultured oligodendrocytes isolated from ovine brains develop and maintain features characteristic of mature oligodendrocytes in situ and can be used to explore formation and maintenance of tight junctions and possibly other classes of cell-cell interactions important in the process of myelination.

Animals↗
PubMed2004

Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis.

Intercellular junctions mediate adhesion and communication between adjoining endothelial and epithelial cells. In the endothelium, junctional complexes comprise tight junctions, adherens junctions, and gap junctions. The expression and organization of these complexes depend on the type of vessels and the permeability requirements of perfused organs. Gap junctions are communication structures, which allow the passage of small molecular weight solutes between neighboring cells. Tight junctions serve the major functional purpose of providing a "barrier" and a "fence" within the membrane, by regulating paracellular permeability and maintaining cell polarity. Adherens junctions play an important role in contact inhibition of endothelial cell growth, paracellular permeability to circulating leukocytes and solutes. In addition, they are required for a correct organization of new vessels in angiogenesis. Extensive research in the past decade has identified several molecular components of the tight and adherens junctions, including integral membrane and intracellular proteins. These proteins interact both among themselves and with other molecules. Here, we review the individual molecules of junctions and their complex network of interactions. We also emphasize how the molecular architectures and interactions may represent a mechanistic basis for the function and regulation of junctions, focusing on junction assembly and permeability regulation. Finally, we analyze in vivo studies and highlight information that specifically relates to the role of junctions in vascular endothelial cells.

Adherens Junctions↗
PubMed1996

Comparison between the distribution of 7H6 tight junction-associated antigen and occludin during the development of chick intestine.

7H6 antigen is a novel tight junction-associated protein first identified in our laboratory with a monoclonal antibody generated by immunizing mice with a bile canaliculus-rich membrane fraction obtained from adult rat liver. Although the antigen is found preferentially at the tight junction of epithelial cells in various organs in adult mammals, the relationship between 7H6 antigen and other tight junction proteins remains obscure. In the present study we examined the relationship between the immunohistochemical distribution of 7H6 antigen and occludin in chick intestinal epithelial cells during development in vivo, since occludin is the only known membrane protein composing tight junctions which is found thus far exclusively in avian tissues. 7H6 antigen was found as coarse dots along the basolateral cell membrane of intestinal epithelium in the chick embryo, whereas it was found as a fine dashed line along the cell border in the chicken. In contrast, occludin was found linearly together with ZO-1 at the cell border of intestinal epithelia both in the chick embryo and chicken. The possible significance of such different localization is briefly discussed.

Animals↗
PubMed1991

Ultrastructural study on junctional complexes of the excurrent duct epithelia in the epididymal region in the fowl.

Junctional complexes of the epithelia lining the rete testis, efferent ductules, connecting ductules and epididymal duct in the fowl were examined by transmission electron microscopy and by a tracer method using lanthanum nitrate. The junctional complexes were composed of tight junctions, adhering junctions and desmosomes. In the rete testis, one or two points of membrane fusion were observed at the tight junctions. In the efferent and connecting ductules and epididymal duct, the tight junctions consisted of a series of punctate membrane fusions. The adhering junctions and desmosomes showed no remarkable structural differences among these excurrent ducts. Vascularly infused lanthanum nitrate penetrated into the tight junctions of individual epithelia for variable distances, but was prevented from entering the lumen at the site of membrane fusion. These results suggest that the tight junctions can restrict the diffusion of materials via the paracellular route, and that they play an important role in maintaining a suitable fluid environment within the excurrent ducts.

Animals↗
PubMed1998

Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration.

Tight junctions are the most apical components of endothelial and epithelial intercellular cleft. In the endothelium these structures play an important role in the control of paracellular permeability to circulating cells and solutes. The only known integral membrane protein localized at sites of membrane-membrane interaction of tight junctions is occludin, which is linked inside the cells to a complex network of cytoskeletal and signaling proteins. We report here the identification of a novel protein (junctional adhesion molecule [JAM]) that is selectively concentrated at intercellular junctions of endothelial and epithelial cells of different origins. Confocal and immunoelectron microscopy shows that JAM codistributes with tight junction components at the apical region of the intercellular cleft. A cDNA clone encoding JAM defines a novel immunoglobulin gene superfamily member that consists of two V-type Ig domains. An mAb directed to JAM (BV11) was found to inhibit spontaneous and chemokine-induced monocyte transmigration through an endothelial cell monolayer in vitro. Systemic treatment of mice with BV11 mAb blocked monocyte infiltration upon chemokine administration in subcutaneous air pouches. Thus, JAM is a new component of endothelial and epithelial junctions that play a role in regulating monocyte transmigration.

Amino Acid Sequence↗
PubMed1973

Cell contacts in the mouse mammary gland. I. Normal gland in postnatal development and the secretory cycle.

The nature and distribution of cell contacts have been examined in thin sections and freeze-fracture replicas of mammary gland samples from female C3H/Crgl mice at stages from birth through pregnancy, lactation, and postweaning involution. Epithelial cells of major mammary ducts at all stages examined are linked at their luminal borders by junctional complexes consisting of tight junctions, variable intermediate junctions, occasional small gap junctions, and one or more series of desmosomes. Scattered desmosomes and gap junctions link ductal epithelial and myoepithelial cells in all combinations; hemidesmosomes attach myoepithelial cells to the basal lamina. Freeze-fracture replicas confirm the erratic distribution of gap junctions and reveal a loose, irregular network of ridges comprising the continuous tight-junctional belts. Alveoli develop early in gestation and initially resemble ducts. Later, as alveoli and small ducts become actively secretory, they lose all desmosomes and most intermediate junctions, whereas tight and gap junctions persist, The tight-junctional network becomes compact and orderly, its undulating ridges oriented predominantly parallel to the luminal surface. It is suggested that these changes in junctional morphology, occurring in secretory cells around parturition, may be related to the greatly enhanced rate of movement of milk precursors and products through the lactating epithelium, or to the profound and recurrent changes in shape of secretory cells that occur in relation to myoepithelial cell contraction, or to both.

Animals↗
PubMed1992

Tight endothelial junctions in the developing microvasculature: a thin section and freeze-fracture study in the chick embryo optic tectum.

The development of the interendothelial tight junctions was studied in the microvessels of the otpic tectum of chick embryos, at the 14th-16th and 18th-20th incubation day (i.d.), and in post-hatching chickens, using thin sections and freeze-fracture techniques. At the 14th-16th i.d., the junctional plasmamembranes of the endothelial cells are simply apposed or fused for brief tracts showing a pentalaminar or trilaminar configuration. In the replicas the P-faces of the fractured junctional membranes are either lacking in intramembrane particles (IMPs) and characterized by finger-like depressions, or provided with discrete IMPs aligned in rows. At the 18th-20th i.d., the thin peripheral expansions of the endothelial cells are superimposed and welded by continuous pentalaminar junctions. Their fracture P-faces display junctional strands formed by parallel fibrils of fused IMPs, with or without interconnections. In the 10-day-old chickens the junctions consist of highly complex networks of fibrils. The results have made it possible to recognize precise relationships between the features of the developing endothelial junctions in the ultrathin sections and, respectively, in the replicas. Moreover, the observations suggest that tight junction formation occurs progressively in the cerebral microvessels by processes of alignment and fusion of the IMPs, which conclude with the arrangement of fibrils in networks.

Animals↗
PubMed2006

Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity.

In this report, sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, is shown to activate tight-junction-associated protein Zonula Occludens-1 (ZO-1), which in turn plays a critical role in regulating endothelial chemotaxis and barrier integrity. After S1P stimulation, ZO-1 was redistributed to the lamellipodia and cell-cell junctions via the S1P1/G(i)/Akt/Rac pathway. Similarly, both endothelial barrier integrity and cell motility were significantly enhanced in S1P-treated cells through the G(i)/Akt/Rac pathway. Importantly, S1P-enhanced barrier integrity and cell migration were abrogated in ZO-1 knockdown cells, indicating ZO-1 is functionally indispensable for these processes. To investigate the underlying mechanisms, we demonstrated that cortactin plays a critical role in S1P-induced ZO-1 redistribution to the lamellipodia. In addition, S1P significantly induced the formation of endothelial tight junctions. ZO-1 and alpha-catenin polypeptides were colocalized in S1P-induced junctional structures; whereas, cortactin was not observed in these regions. Together, these results suggest that S1P induces the formation of two distinct ZO-1 complexes to regulate two different endothelial functions: ZO-1/cortactin complexes to regulate chemotactic response and ZO-1/alpha-catenin complexes to regulate endothelial barrier integrity. The concerted operation of these two ZO-1 complexes may coordinate two important S1P-mediated functions, i.e. migration and barrier integrity, in vascular endothelial cells.

Cell Adhesion↗
PubMed2004

A peculiar internalization of claudins, tight junction-specific adhesion molecules, during the intercellular movement of epithelial cells.

Tight junctions (TJs) seal the intercellular space of epithelial cells, while individual epithelial cells move against adjacent cells in cellular sheets. To observe TJs in live epithelial cellular sheets, green fluorescent protein (GFP) was fused to the N-terminus of claudin-3 (a major cell adhesion molecule of TJs), which was stably expressed at a level that was approximately 50% of that of endogenous claudin-3 in mouse Eph4 epithelial cells. Under confluent culture conditions, individual cells moved within cellular sheets, which was associated with the remodeling of TJs. However, during this remodeling, GFP-positive TJs did not lose their structural continuity. When TJs between two adjacent cells decreased in length during this remodeling, GFP-claudin-3 was frequently pinched off as a granular structure from GFP-positive TJs together with endogenous claudins. Co-culture experiments, as well as electron microscopy, revealed that the two apposed membranes of TJs were not detached, but co-endocytosed into one of the adjacent cells. Interestingly, other TJ components such as occludin, JAM and ZO-1 appeared to be dissociated from claudins before this endocytosis. The endocytosis of claudins was facilitated when the intercellular motility was upregulated by wounding the cellular sheets. These findings suggest that this peculiar internalization of claudins plays a crucial role in the remodeling of TJs, and that the fine regulation of this endocytosis is important for TJs to seal the intercellular space of epithelial cells that are moving against adjacent cells within cellular sheets.

Animals↗
PubMed1983

Glial membrane specializations and the compartmentalization of the lamina ganglionaris of the housefly compound eye.

Membrane specializations in the lamina ganglionaris of the housefly are investigated using conventional thin-section EM, freeze-fracture replication and the diffusion of colloidal lanthanum. All glial cells in the lamina are coupled by gap junctions. Desmosomes also link all glia except the epithelial glia. Extensive glia-glial and glia-neuronal septate junctions are present in the pseudocartridge zone and nuclear layer. Septate junctions in the nuclear layer intermingle with bands of interglial and glia-neuronal tight junctions. Tight junctions are also found between satellite and epithelial glia at the border of the nuclear and plexiform layers, between adjacent epithelial glial cells in the plexiform layer, between epithelial and marginal glia at the proximal boundary of the optic neuropil, between marginal glial cells, and between marginal glia and axons. Colloidal lanthanum, introduced through an incision in the cornea, penetrates the retina but is occluded from the neuropil by septate junctions in the pseudocartridge zone. The disposition of tight and septate junctions is described in relation to the compartmentalization of the lamina. Two major compartments are delineated. The first represents the nuclear layer and contains the cell bodies of second-order visual neurons (monopolar neurons). The second compartment constitutes the plexiform layer of the lamina. Within the plexiform layer, each optic cartridge is partitioned into a separate subcompartment. Also, tracheoles and axons of long visual fibres are isolated from the optic cartridges by glial tight junctions. Morphological evidence for compartmentalization is correlated with previously established electrical properties of the insect lamina ganglionaris.

Animals↗
PubMed1978

A freeze-fracture and lanthanum tracer study of the complex junction between Sertoli cells of the canine testis.

What appear to be true septate junctions by all techniques currently available for the cytological identification of intercellular junctions are part of a complex junction that interconnects the Sertoli cells of the canine testis. In the seminiferous epithelium, septate junctions are located basal to belts of tight junctions. In thin sections, septate junctions appear as double, parallel, transverse connections or septa spanning an approximately 90-A intercellular space between adjacent Sertoli cells. In en face sections of lanthanum-aldehyde-perfused specimens, the septa themselves exclude lanthanum and appear as electron-lucent lines arranged in a series of double, parallel rows on a background of electron-dense lanthanum. In freeze-fracture replicas this vertebrate septate junction appears as double, parallel rows of individual or fused particles which conform to the distribution of the intercellular septa. Septate junctions can be clearly distinguished from tight junctions as tight junctions prevent the movement of lanthanum tracer toward the lumen, appear as single rows of individual or fused particles in interlacing patterns within freeze-fracture replicas, and are seen as areas of close membrane apposition in thin sections. Both the septate junction and the tight junction are associated with specializations of the Sertoli cell cytoplasm. This is the first demonstration in a vertebrate tissue of a true septate junction.

Animals↗
PubMed2000

HGF/SF-induced spreading of MDCK cells correlates with disappearance of barmotin/7H6, a tight junction-associated protein, from the cell membrane.

Changes in expression of the two tight junction-associated proteins, barmotin/7H6 and ZO-1, as well as the adherence junction-associated protein, E-cadherin, were followed during hepatocyte growth factor/scatter factor (HGF/SC)-induced migration process of MDCK cells. Modulation of the HGF/SF-induced migration process by staurosporine, an inhibitor of protein kinase C (PKC), was also examined. Cell migration induced by HGF/SF consisted of two distinct phases, initial cell spreading between 2 and 9 h after the start of treatment, and the scattering phase which started approximately 12 h after treatment. Both ZO-1 and E-cadherin were expressed at the cell-cell border of adherent cells in the scattering phase, whereas barmotin/7H6, a barrier function-related tight junction protein, was not seen during the early spreading phase. Confluent cultures of MDCK cells, which did not spread after HGF/SF treatment, were positive for barmotin/7H6 expression at cell-cell borders. Blocking PKC activation during HGF/SF treatment with staurosporine inhibited cell spreading, and the cells retained barmotin/7H6 expression until at 6 h after HGF/SF treatment. The results indicate that disappearance of the tight junction protein, barmotin/7H6, is closely associated with cell spreading, with both barmotin/7H6 expression and cell spreading seemingly being regulated by PKC-mediated signaling.

Animals↗
PubMed1994

Distribution of the tight junction-associated protein ZO-1 in circumventricular organs of the CNS.

The immunofluorescent distribution of ZO-1, a tight junction-associated protein, was studied in murine circumventricular organs. These regions generally express a less restrictive blood-brain barrier than is found in other areas of the CNS. In the remaining brain parenchyma, where a characteristic blood-brain barrier exists, ZO-1 was localized in discrete, continuous lines along blood vessels, presumably in association with endothelial cell tight junctions. The ependymal cells in the ventricular walls displayed a more punctate pattern of ZO-1 distribution, indicative of discontinuous tight junctions. In two of the circumventricular organs examined, the median eminence and the subfornical organ, many capillaries lacked detectable ZO-1 immunoreactivity while the apical aspects of the specialized ependymal cells (tanycytes) revealed an unbroken ZO-1 distribution. Scant labelling of ZO-1 in blood vessels was found in the area postrema, and only weak and discontinuous ZO-1 labelling was present in the ventricular wall. Capillaries of the organum vasculosum laminae terminalis expressed ZO-1 immunoreactivity which was comparable to the pattern observed in CNS regions with typical blood-brain barrier. The subcommissural organ, known to contain a blood-brain barrier, also displayed continuous ZO-1 staining in blood vessels. Unbroken ZO-1 distribution was observed in the specialized ependymal cells adjacent to both the organum vasculosum laminae terminalis and subcommissural organ. These immunocytochemical data demonstrate a distribution of ZO-1 in CNS parenchyma outside the circumventricular organs that is consistent with an organization of tight junctions which prevent free paracellular exchange of substances between blood and neuropil but which allow for continuity between CSF and the neuronal environment. The ZO-1 staining pattern in blood vessels and ventricular walls of the circumventricular organs is heterogeneous despite the prevalent absence of a functional blood-brain barrier.

Animals↗
PubMed2006

Claudins in occluding junctions of humans and flies.

The epithelial barrier is fundamental to the physiology of most metazoan organ systems. Occluding junctions, including vertebrate tight junctions and invertebrate septate junctions, contribute to the epithelial barrier function by restricting free diffusion of solutes through the paracellular route. The recent identification and characterization of claudins, which are tight junction-associated adhesion molecules, gives insight into the molecular architecture of tight junctions and their barrier-forming mechanism in vertebrates. Mice lacking the expression of various claudins, and human hereditary diseases with claudin mutations, have revealed that the claudin-based barrier function of tight junctions is indispensable in vivo. Interestingly, claudin-like molecules have recently been identified in septate junctions of Drosophila. Here, we present an overview of recent progress in claudin studies conducted in mammals and flies.

Animals↗
PubMed1996

Localization of 7H6 tight junction-associated antigen along the cell border of vascular endothelial cells correlates with paracellular barrier function against ions, large molecules, and cancer cells.

To study the regulation of the endothelial barrier, we examined the relationship between the paracellular barrier function and the expression of 7H6 antigen localized at tight junctions of endothelial cells by using transendothelial electrical resistance (TER), fluxes of albumin and dextran, transmigration of rat mammary cancer (SST-2) cells across rat lung endothelial (RLE) cells, and immunocytochemical expression of 7H6 antigen as parameters. RLE cells cultured at a confluent cell density did not express immunohistochemically demonstrable 7H6 antigen and had low paracellular barrier functions. However, treatment of the endothelial cells with 0.5 mM dibutyryl-cAMP or 10(-6) M all-trans-retinoic acid for 4 days induced 7H6 antigen preferentially at the cell border and simultaneously enhanced the barrier function twofold, in terms of TER and fluxes of albumin and dextran. Furthermore, RA-treated RLE cell monolayers with the enhanced barrier function significantly inhibited the transmigration of SST-2 cells. These results together with those of our previous study indicate that 7H6 antigen has a crucial role in the regulation of paracellular barrier function not only in epithelial cells but also in vascular endothelial cells. The present study also suggests that tight junctions of vascular endothelium in vivo function as a barrier between blood and tissues against metastatic cancer cells.

Animals↗
PubMed2004

HPAF-II, a cell culture model to study pancreatic epithelial cell structure and function.

OBJECTIVES: Epithelial cells have distinct apical and basolateral plasma membrane domains separated by tight junctions. This phenotype is essential for the directional transport functions of epithelial cells. Here we characterized a well-differentiated pancreatic epithelial cell line to establish a useful model for understanding the mechanisms involved in the regulation of junctional complexes, polarity, and disease processes in the pancreas. METHODS: Immunofluorescence of cell junction marker proteins and electron microscopy were used to determine the presence of tight junctions, adherens junctions, and desmosomes. The functionality of tight junctions was tested by transepithelial resistance measurements and transepithelial permeability studies of nonionic molecules. Tight junction function in polarity was determined by laser scanning confocal microscopy. RESULTS: Immunofluorescence analysis in HPAF-II cells revealed tight junction localization of ZO-1, occludin, and claudin-4; adherens junction localization of E-cadherin and beta-catenin; and desmosomal localization of desmocollin. Transmission electron microscopy showed the presence of tight junctions, adherens junctions, and des-mosomes, and freeze-fracture electron microscopy revealed the presence of distinct anastomosing tight junction strands. Transepithelial electrical resistance and permeability measurements revealed functional tight junctions. In addition, 3-dimensional images of the monolayer generated by laser scanning confocal microscopy revealed that HPAF-II cells show polarity. Immunoblotting and RT-PCR analyses revealed high expression levels of E-cadherin and Na,K-ATPase beta-subunit but low levels of the transcription factor Snail in HPAF-II cells compared with MiaPaCa-2 cells. CONCLUSION: The HPAF-II cell line is a well-differentiated human pancreatic carcinoma cell line that should be useful as a model for studies aimed at understanding epithelial polarity, regulation of junctional complexes, and disease processes in pancreas.

Adherens Junctions↗
PubMed2003

Comparison of ultrastructure, tight junction-related protein expression and barrier function of human corneal epithelial cells cultivated on amniotic membrane with and without air-lifting.

PURPOSE: To evaluate the usefulness of the air-lifting technique for culturing corneal limbal epithelial cells on amniotic membrane (AM) for use in ocular surface reconstruction. A cultured sheet that has a good barrier function should be better for this purpose. In corneal epithelium, tight junctions (TJ) play a vital role in the barrier function. The TJ complex includes the integral transmembrane proteins occludin and the claudins, and some membrane-associated proteins such as ZO-1. In this paper, we investigated the barrier function and the expression of TJ related proteins. METHODS: Corneal limbal epithelium obtained from donor corneas and cultivated on acellular AM was divided into two groups. These were the non-air-lifting (Non-AL) group, which was continuously submerged in medium, and the air-lifting (AL) group, which was submerged in medium for 3 weeks, then exposed to air by lowering the medium level. Morphology and the permeability to horseradish peroxidase (HRP) were determined by electron microscopy. Tight junction (TJ)-related protein and mRNA expression changes were assessed by immunoblotting and reverse transcription-polymerase chain reaction. RESULTS: The cultures of both groups formed 4-5-layer-thick, well-stratified epithelium. The AL cultures had tightly packed epithelial cells with all the HRP/diaminobenzidine (DAB) reaction product accumulated on the apical surface of the superficial cells. The Non-AL culture, by contrast, had more loosely packed epithelial cells with larger intercellular spaces. The HRP/DAB reaction product penetrated the intercellular space to a depth of 3-4 cell layers. Statistically, there was a significant difference in intercellular spaces and desmosome count in the superficial cells between the groups. With AL, TJ-related proteins localized at the apical portion of the lateral membrane. TJ-related protein and mRNA amounts were not changed by AL while claudin subtype expression became more consistent and closer to that of in vivo corneal epithelium. CONCLUSIONS: The AL technique reduces intercellular spaces in the superficial cells and promotes the formation of the barrier function. It is useful in culturing corneal epithelial cells for use in ocular surface reconstruction.

Amnion↗
PubMed2005

Signaling the junctions in gut epithelium.

This Perspective summarizes recent developments in our understanding of the signaling pathways involved in the regulation of epithelial cell adhesion in the gut. The role of phosphatidylinositol 3-kinase signaling in the modulation of adherens junctions, and the connections between tight junctions and nuclear transcription factors, are discussed. The effect of gastrins on adherens and tight junctions is presented as an example of the regulation of adhesion by growth factors. The consequences of dysregulation of adherens junctions and tight junctions for human pathology are also considered.

Adherens Junctions↗