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PubMed1986

The ultrastructure of the rat primary decidual zone.

The rat primary decidual zone (PDZ) is a transitory, avascular region of transformed fibroblasts surrounding the implanting embryo. Tracer studies have indicated that the PDZ is selectively permeable to macromolecules, permeability decreasing with increasing molecular weight of the tracer. To clarify the morphological basis of the permeability barrier, we have studied the ultrastructure of the PDZ with particular emphasis on the intercellular features and cellular junctions. The cells of the PDZ were large and tightly packed; their apposed membranes showed extensive interdigitations in some regions, but elsewhere they were relatively straight. Tight junctions, gap junctions, and desmosomelike junctions were observed between decidual cells. The tight junctions usually consisted of one or two points of membrane fusion, and they were oriented both parallel and perpendicular to the long axis of the PDZ. These junctions were frequently associated with gap junctions. Scattered pockets of dilated extracellular space between decidual cells contained collagen fibrils and an amorphous, dense material. These extracellular components were also sequestered by the decidual cells in deep invaginations of the cell surface that were continuous with the extracellular space. Decidual cells also exhibited flangelike processes that penetrated the basal laminae of the adjacent epithelium and capillary endothelium. Our present observations indicate that decidual cells are connected by tight junctions, and a previous study demonstrated that macromolecules up to 40 kDa readily cross the PDZ; hence, the tight junctions appear to be discontinuous. We suggest that the structures restricting the movement of large macromolecules (66 kDa and larger) across the PDZ from blood vessels to the embryo may include discontinuous tight junctions, membrane interdigitations, and amorphous intercellular material.

Animals↗

PubMed2004

Extracellular signal-regulated kinases 1/2 control claudin-2 expression in Madin-Darby canine kidney strain I and II cells.

The tight junction of the epithelial cell determines the characteristics of paracellular permeability across epithelium. Recent work points toward the claudin family of tight junction proteins as leading candidates for the molecular components that regulate paracellular permeability properties in epithelial tissues. Madin-Darby canine kidney (MDCK) strain I and II cells are models for the study of tight junctions and based on transepithelial electrical resistance (TER) contain "tight" and "leaky" tight junctions, respectively. Overexpression studies suggest that tight junction leakiness in these two strains of MDCK cells is conferred by expression of the tight junction protein claudin-2. Extracellular signal-regulated kinase (ERK) 1/2 activation by hepatocyte growth factor treatment of MDCK strain II cells inhibited claudin-2 expression and transiently increased TER. This process was blocked by the ERK 1/2 inhibitor U0126. Transfection of constitutively active mitogen-activated protein kinase/extracellular signal-regulated kinase kinase into MDCK strain II cells also inhibited claudin-2 expression and increased TER. MDCK strain I cells have higher levels of active ERK 1/2 than do MDCK strain II cells. U0126 treatment of MDCK strain I cells decreased active ERK 1/2 levels, induced expression of claudin-2 protein, and decreased TER by approximately 20-fold. U0126 treatment also induced claudin-2 expression and decreased TER in a high resistance mouse cortical collecting duct cell line (94D). These data show for the first time that the ERK 1/2 signaling pathway negatively controls claudin-2 expression in mammalian renal epithelial cells and provide evidence for regulation of tight junction paracellular transport by alterations in claudin composition within tight junction complexes.

Animals↗

PubMed1983

Intercellular junctions in hepatocellular carcinoma.

The freeze-fracture technique has been used to study the organization of intercellular junctions in two cases of hepatocellular carcinoma. A tumor free cirrhotic liver has been included for comparison. Tight junctions were disorganized in the tumor cells of hepatocellular carcinoma. The tight junction networks often were not orientated parallel to the canalicular lumen. In some areas tight junctions comprised 2 to 4 strands, while in other areas they were reduced to a single strand. Discontinuities and local proliferation of tight junctions were also seen. Some tight junctions were composed of intramembrane particles aligned to form a discontinuous network. Gap junctions between the tumor cells were small and infrequent. Gap junctions were found only on the lateral plasma membranes and were not seen within the tight junction networks. These findings have been interpreted to indicate changes in intercellular communication, and an alteration in the ability of hepatocytes to differentiate tight junctions in hepatocellular carcinoma.

Carcinoma, Hepatocellular↗

PubMed2005

The role of junctional adhesion molecules in cell-cell interactions.

Cell-cell-interactions are important for the regulation of tissue integrity, the generation of barriers between different tissues and body compartments thereby providing an effective defence against toxic or pathogenic agents, as well as for the regulation of inflammatory cell recruitment. Intercellular interactions are regulated by adhesion receptors on adjacent cells which upon extracellular ligand binding mediate intracellular signals. In the vasculature, neighbouring endothelial cells interact with each other through various adhesion molecules leading to the generation of junctional complexes like tight junctions (TJs) and adherens junctions (AJs) which regulate both leukocyte endothelial interactions and paracellular permeability. In this context, emerging evidence points to the importance of the family of junctional adhesion molecules (JAMs), which are localized in tight junctions of endothelial and epithelial cells and are implicated in the regulation of both leukocyte extravasation as well as junction formation and permeability.

Animals↗

PubMed1984

Membrane events involved in fusion of uterine epithelial cells in pseudopregnant rabbits.

During pseudopregnancy in the rabbit some uterine epithelial cells undergo conversion into symplasmata. This event serves as a model for studies of membrane apposition, fusion and fission of the lateral membranes with the use of different ultrastructural techniques. Apposition of lateral membranes occurs by means of proliferation of the tight-junctional belt and macular tight junctions. Membrane fusion is characterized in freeze-fracture replicas by continuously running fracture planes between neighboring membrane leaflets of epithelial cells, in general without reorganization of the particles. It is suggested that the reorganization of particles as well as the blebs or vesicles of smooth membranes, which are occasionally observed, may be artefacts. Membrane fission occurs simultaneously with fusion resulting in irregularly shaped membrane holes on freeze-fracture replicas. These events are rarely seen in thin sections. Staining with tannic acid reveals that only the layers of the plasma membrane are accessible to this agent. The fusion-fission process starts in the lower region of the lateral membranes, whereas the luminal portion with the broad tight-junctional belt remains intact.

Animals↗

PubMed2006

Microtubules regulate disassembly of epithelial apical junctions.

BACKGROUND: Epithelial tight junction (TJ) and adherens junction (AJ) form the apical junctional complex (AJC) which regulates cell-cell adhesion, paracellular permeability and cell polarity. The AJC is anchored on cytoskeletal structures including actin microfilaments and microtubules. Such cytoskeletal interactions are thought to be important for the assembly and remodeling of apical junctions. In the present study, we investigated the role of microtubules in disassembly of the AJC in intestinal epithelial cells using a model of extracellular calcium depletion. RESULTS: Calcium depletion resulted in disruption and internalization of epithelial TJs and AJs along with reorganization of perijunctional F-actin into contractile rings. Microtubules reorganized into dense plaques positioned inside such F-actin rings. Depolymerization of microtubules with nocodazole prevented junctional disassembly and F-actin ring formation. Stabilization of microtubules with either docetaxel or pacitaxel blocked contraction of F-actin rings and attenuated internalization of junctional proteins into a subapical cytosolic compartment. Likewise, pharmacological inhibition of microtubule motors, kinesins, prevented contraction of F-actin rings and attenuated disassembly of apical junctions. Kinesin-1 was enriched at the AJC in cultured epithelial cells and it also accumulated at epithelial cell-cell contacts in normal human colonic mucosa. Furthermore, immunoprecipitation experiments demonstrated association of kinesin-1 with the E-cadherin-catenin complex. CONCLUSION: Our data suggest that microtubules play a role in disassembly of the AJC during calcium depletion by regulating formation of contractile F-actin rings and internalization of AJ/TJ proteins.

Actin Cytoskeleton↗

PubMed2004

Tight junction-associated proteins (occludin, ZO-1, claudin-1, claudin-4) in squamous cell carcinoma and Bowen's disease.

BACKGROUND: The epidermis, which is a typical stratified epithelium, has tight junctions (TJs) in the granular layer, as do simple epithelia. So far, abnormalities of TJs and involvement of claudin-1 have been reported in tumours of simple epithelia. OBJECTIVES: To examine the expression of TJ-associated proteins (occludin, ZO-1, claudin-1 and claudin-4) in normal human epidermis and in malignant disorders of keratinization. METHODS: Expression of the proteins in normal human epidermis, five cases of squamous cell carcinoma (SCC) of the skin and five cases of Bowen's disease (BD) was examined by immunofluorescence staining. RESULTS: In normal human epidermis, occludin, ZO-1 and claudin-4 were expressed at the cell-cell borders in the granular layer specifically or dominantly, whereas claudin-1 was expressed in the whole epithelium. In SCC, occludin, ZO-1, claudin-1 and claudin-4 were strongly expressed in tumour cells with keratinization such as cancer pearls. Claudin-1 was heterogeneously expressed in unkeratinized tumour cells, whereas expression of occludin, ZO-1 and claudin-4 was decreased or absent. In BD, aberrant expression of occludin, ZO-1, claudin-1 and claudin-4 was observed at the cell-cell borders in addition to their expression patterns observed in normal epidermis. CONCLUSIONS: Expression of occludin, ZO-1 and claudin-4 is associated with keratinization in SCC and BD. However, the heterogeneous expression of claudin-1 in SCC is not determined only by keratinization.

Aged↗

PubMed1988

Development of membrane interactions between brain endothelial cells and astrocytes in vitro.

To ascertain whether there is a mutual influence on the structure of their cell membranes, brain endothelial cells and their closest neighbor, astrocytes, were grown alone or together in vitro and freeze-fractured. When cultured separately, the brain endothelial cells had a low frequency of short, fragmented tight junctions. Many gap junctions, which are absent from mature brain capillaries in vivo, intercalated among the tight junctional strands, or were separate from them. The separately cultured astrocytes had low concentrations of randomly distributed assemblies (1-30/micron2) in their membranes. When the two cell types were co-cultured, the endothelial tight junctions were greatly enhanced in frequency, length, width and complexity, and the gap junctional area enclosed by the tight junctional strands were markedly reduced. Thus, the in vitro endothelial junctional complex resembled their in vivo counterpart, the tight junctions of brain capillaries, when co-cultured with astrocytes. Reciprocally, brain endothelial cells induced the astrocytic membrane assemblies to increase in concentrations by approximately 5 fold, and sometimes to form aggregates with very high concentrations (400/micron 2) which approached the concentration of the perivascular astrocytic membranes in vivo. Substituting astrocytes with fibroblasts or smooth muscle cells in co-cultures did not enhance the tight junctions in the brain endothelium. On the other hand, substituting brain endothelium with endothelium from pulmonary artery or aorta in co-cultures did not increase the concentration or induce aggregation of the assemblies in the astrocytes. Thus, the two close neighbors in vivo, brain endothelium and astrocytes, interact specifically in vitro to induce development of membrane specializations which resemble those at the site of the blood-brain barrier.

Animals↗

PubMed1990

Extrusion of colonic epithelial cells in vitro.

Rat colonic mucosae fixed in situ in Ussing chambers provided a model of the extrusion of absorptive enterocytes and less commonly of goblet and enteroendocrine cells. The cells were lost at extrusion zones midway between crypt mouths. Even in mucosae in which the number of extruding cells was large, epithelial continuity was maintained as evaluated morphologically and electrophysiologically. Beneath points of remaining contact between desquamating cells and the epithelial sheet, microfilaments of the terminal web formed band-like structures linking adjacent junctional complexes. Freeze-fracture replicas disclosed extensive macular regions of tight junction strands in the plasma membranes of desquamating cells. Tight junctions between newly neighboring cells were often irregular and often occurred beneath the terminal web region. Dithiothreitol enhanced cell loss and increased basal epithelial conductance, but histological continuity was maintained and the mucosae continued to respond typically to bradykinin. These observations suggest that during the loss of senescent enterocytes, tight junctions are maintained; old junctional elements are lost, and tight junctions are formed between remaining adjacent cells. This model offers a means to study the synthesis and turnover of tight junctions and the maintenance of the colonic epithelial barrier.

Animals↗

PubMed1999

Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins.

ZO-1, ZO-2, and ZO-3, which contain three PDZ domains (PDZ1 to -3), are concentrated at tight junctions (TJs) in epithelial cells. TJ strands are mainly composed of two distinct types of four-transmembrane proteins, occludin, and claudins, between which occludin was reported to directly bind to ZO-1/ZO-2/ZO-3. However, in occludin-deficient intestinal epithelial cells, ZO-1/ZO-2/ZO-3 were still recruited to TJs. We then examined the possible interactions between ZO-1/ZO-2/ZO-3 and claudins. ZO-1, ZO-2, and ZO-3 bound to the COOH-terminal YV sequence of claudin-1 to -8 through their PDZ1 domains in vitro. Then, claudin-1 or -2 was transfected into L fibroblasts, which express ZO-1 but not ZO-2 or ZO-3. Claudin-1 and -2 were concentrated at cell-cell borders in an elaborate network pattern, to which endogenous ZO-1 was recruited. When ZO-2 or ZO-3 were further transfected, both were recruited to the claudin-based networks together with endogenous ZO-1. Detailed analyses showed that ZO-2 and ZO-3 are recruited to the claudin-based networks through PDZ2 (ZO-2 or ZO-3)/PDZ2 (endogenous ZO-1) and PDZ1 (ZO-2 or ZO-3)/COOH-terminal YV (claudins) interactions. In good agreement, PDZ1 and PDZ2 domains of ZO-1/ZO-2/ZO-3 were also recruited to claudin-based TJs, when introduced into cultured epithelial cells. The possible molecular architecture of TJ plaque structures is discussed.

Amino Acid Motifs↗

PubMed2005

erbB1 functions as a sensor of airway epithelial integrity by regulation of protein phosphatase 2A activity.

Two enzymes, protein phosphatase 2A and atypical protein kinase C, are associated with the tight junction and regulate its function. For example, phosphorylation of the tight junction protein occludin is required for its incorporation into the junction. The association of a kinase and phosphatase with the tight junction suggests that a balance between their activities exists and is required for normal tight junction function. This hypothesis predicts that loss of epithelial integrity may disrupt this balance in such a way as to facilitate restoration of epithelial integrity. Our previous data have shown that apically localized growth factors segregate from their basolaterally localized erbB receptors. Loss of epithelial integrity allows ligand access to the basolateral membrane where it immediately binds to and activates erbB receptors. We found that activation of erbB1 leads to phosphorylation of protein phosphatase 2A, inhibiting its activity. Importantly, this phosphorylation event was dependent on factors in the overlying airway surface liquid; washing away this liquid prevented phosphorylation. erbB1-mediated inhibition of phosphatase activity would shift the balance in favor of the kinase such that tight junction proteins would regain their phosphorylation, allowing for their incorporation into the junction complex. This mechanism provides a rapid means of sensing the loss of epithelial integrity and subsequently restoring barrier function.

ErbB Receptors↗

PubMed1980

Intercellular junctions in the uterine epithelium of Salamandra salamandra (L.) (Amphibia, Urodela). A freeze-fracture study.

Intercellular junctions in the uterine epithelium of the ovoviviparous urodele Salamandra salamandra were studied in pregnant and non-pregnant females by freeze-fracture technique. Junctional complexes consist of zonulae occludentes (tight junctions) and numerous maculae adhaerentes (desmosomes); z. adhaerentes and nexuses (gap junctions) could not be identified. Tight junctions are of the "flexible" type exhibiting loosely interconnected fibrils. The fibrillary network appears stretched more often in pregnant females possibly due to the mechanical stress of pregnancy. The structure and occurrence of the junctions identified, especially that of the tight junctions, is discussed with regard to the functions of the uterus during pregnancy.

Animals↗

PubMed2003

Tight junction-related protein expression and distribution in human corneal epithelium.

PURPOSE: To investigate the expression and cellular distribution of the tight junction-related proteins occludin, claudin and ZO-1 in human corneal epithelium. METHODS: Light and electron immunohistochemistry was used to determine tissue distribution of occludin, claudin-1 and ZO-1 in the human corneal epithelium. Reverse transcription-polymerase chain reaction was used to reveal claudin mRNA expression in human corneal epithelium. RESULTS: In transverse sections, occludin and ZO-1 were localized at the apical cell-cell junctions between superficial cells in stratified corneal epithelium. Both basal and basolateral membranes of superficial cells were stained by the claudin-1 antibody, but no apical membrane staining was observed. In en face sections, claudin-1 and ZO-1 antibodies showed as bands that corresponded to the junctional complex. Claudin-1 staining of superficial cell cytoplasm was also observed. Occludin staining was seen at the junctional complex, where it was not continuous, but dotted along the cell junctions. The transcripts for claudin-1 and several other claudin isotypes, such as -2, -3, -4, -7, -9 and -14 were identified. CONCLUSION: Not only occludin, but also some claudins act as integral transmembrane proteins in the corneal epithelium. ZO-1 is a component of the corneal epithelial tight junction, as it is in most epithelial cells.

Claudin-1↗

PubMedDate not supplied

Membrane specializations in the human organ of Corti.

The human organ of Corti was investigated with the freeze fracturing technique with the purpose of analysing membrane specializations. Tight junctions were found on hair cells as well as on supporting cells. Inner and outer hair cells were coupled to the supporting cells by rather extensive tight junctions. The tight junctions between the Deiter's cells were comparable to those of the hair cells, while the tight junctions between the Hensen's cells were considerably less extensive. Gap junctions were present coupling all supporting elements in the organ of Corti, small ones preferably in the apical regions of the cells and large ones in the basal region.

Freeze Fracturing↗

PubMed1977

Freeze-fracture of capillary endothelium in rat brain.

The rat brain capillary was studied with freeze-fracture technique. The attached plasmalemmal vesicles were quite few in number on the luminal front and sometimes numerous on the contraluminal side. The fracture appearance of some tight junctions showed interconnecting ridges on face A and complementary furrows devoid of particles on face B, comparable to the common tight junction in the normal epithelia. Other tight junctions revealed a preferential disposition of quasicontinous rows of particles on shallow furrows of face B, resembling the tight junctional strands of capillary endothelium in non-cerebral tissues. Either behavior is probably due to the difference in the fracture plane around the single fibril. In addition, the tight junctional strand could surround the perimeter of the endothelial cell completely although the exposed strand of tight junction was limited in lenght.

Animals↗

PubMed1980

[Ultrastructure of the ocular ciliary epithelium of the common frog].

The ultrastructure of the adult frog ciliary epithelium cells has definite regional differences. Cells of ciliary epithelium folds near the iris display morphological features characterizing its barrier and secretory functions which lead to the formation of aqueous humor. These are junctional complexes with tight junctions (zonula occludents) in the apical parts of contacting sides of cells of the inner leaf: a great quantity of mitochondria, ribosomes and various vesicles, well developed endoplasmic reticulum in the cytoplasm, much folded basal surface, gap junctions between cells of external and internal leaflets. In the mammalian inner epithelial layer different cell junctions are known to be arranged in a fixed spatial fashion. Unlike, in the frog's epithelium both zonula adherent and desmosomes may be found in any sequence. Tight junctions are formed during metamorphosis, on the place of focal junctions, whereas gap junctions, referred to earlier as "extended", start functioning between cells just on the very early stages of eye morphogenesis (Dabagyan et al., 1979). The epithelium of the posterior part of the ciliary fold and pars plana of the ciliary body have, in addition, the number of morphological sign indicating the cell involvement in the accomodational function of any eye (i. e. a majority of desmosomes binding all cells together and of zonulae adherentes, well developed intracellular skeleton of tonofilament bundles). These features are characteristic of the whole distal part of ciliary epithelium rather than of the place of attachment of zonula fiber only.

Animals↗

PubMed2006

Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells.

The blood-brain barrier (BBB), a selective barrier formed by endothelial cells and dependent on the presence of tight junctions, is compromised during neuroinflammation. A detailed study of tight junction dynamics during transendothelial migration of leukocytes has been lacking. Therefore, we retrovirally expressed green fluorescent protein (GFP) fused to the N-terminus of the tight junction protein occludin in the rat brain endothelial cell line GP8/3.9. Confocal microscopy analyses revealed that GFP-occludin colocalized with the intracellular tight junction protein, ZO-1, localized at intercellular connections, and was absent at cell borders lacking apposing cells. Using live cell imaging we found that monocytes scroll over the brain endothelial cell surface toward cell-cell contacts, induce gap formation, which is associated with local disappearance of GFP-occludin, and subsequently traverse the endothelium paracellularly. Immunoblot analyses indicated that loss of occludin was due to protein degradation. The broad spectrum matrix metalloproteinase (MMP) inhibitor BB-3103 significantly inhibited endothelial gap formation, occludin loss, and the ability of monocytes to pass the endothelium. Our results provide a novel insight into the mechanism by which leukocytes traverse the BBB and illustrate that therapeutics aimed at the stabilization of the tight junction may be beneficial to resist a neuroinflammatory attack.

Animals↗

PubMed1977

Ultrastructure of the blood-aqueous barrier in normal condition and after paracentesis A freeze-fracture study in the rabbit.

There is in the ciliary epithelium a barrier which prevents the passage of plasma proteins into the posterior chamber of the eye. The anatomical site of this blood-aqueous barrier is at the zonulae occludentes (tight junctions) located between the lateral plasma-membranes of the nonpigmented epithelial cells. Using the freeze-fracture technique we have studied these junctions in the pars plicata. As in many epithelia, they are formed by an anastomosing network of ridges on the fracture PF face and by a complementary set of furrows on the fracture EF face of plasma membranes. Features of these junctions are the presence of frequent parallel and closely associated double or triple ridges, and a few small gap junctions, associated with tight junctional elements of the zonulae occludentes. We also show that the number of junctional strands (ridges and furrows from apex to base) varies from a few strands to about 15, according to their position around the nonpigmented epithelial cells. These observations suggest that the rabbit's ciliary epithelium is to be classified among the 'tight' or 'very tight' epithelia (Claude and Goodenough, 1973). After paracentesis, we observed no breakdown of the zonulae occludentes. This supports the hypothesis that the site of leakage of the plasma proteins is elsewhere than ciliary epithelium.

Animals↗