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PubMed1993

[Spontaneous and induced permeability of the tight junctions in the bladder epithelium of the frog Rana temporaria].

The spontaneous and induced alterations in paracellular permeability of the isolated frog urinary bladder were studied. For estimation of the tight junction (TJ) permeability, a fluorescent dye uranine was used. No morphological or functional evidences for the TJ opening were found in the autumn-winter period, both in the control and after the osmotic flow stimulation by 25 mg/ml pituitrine (P) or serosal mannitol (200 mM). In the spring, a spontaneous uranine efflux through the bladder wall from the mucosal solution was found in parallel with an increase in the basal water flow and a decrease in the responses of the bladder to P and serosal hypertonicity. At the same time, the intercellular substance remained to be a barrier for water. In the autumn-winter the TJ opening could be induced by adding sulfhydryl reagents, p-chloromercury-phenyl-sulfonic acid (PCMPS) or N-ethylmaleimide (NEM), to the serosal solution. However, NEM was effective only when added to the mucosal solution. The uranine efflux induced by sulfhydryl reagents was accompanied with a marked hydroosmotic flow in parallel with a diminished sensitivity to P, the barrier properties of intercellular substances were lost. As evidenced by electron microscopy, PCMPS induced a gradual destruction of TJ structures, while certain cytoplasmic structures were not affected. The uranine efflux in the autumn-winter frogs could be induced by an artificial osmotic gradient after preincubation of the bladders in the isotonic solution with P. Some possible intracellular mechanisms causing both spontaneous and induced alterations in the TJ permeability are discussed.

Animals↗
PubMed1993

Tight junction complexity in the retinal pigment epithelium of the chicken during development.

In the avascular retina of birds, the pigment epithelium (RPE) is the main site of the blood-retina barrier. Tight junctions (TJs) connect the pigment epithelial cells and represent the structural substrate of the barrier function. We investigated, by means of the quantitative freeze-fracturing technique, the TJs of the chicken RPE during development and compared them with the TJs of choroid capillary endothelial cells which are known to be fenestrated. The association of TJs with the protoplasmic membrane leaflet (P-face) is more pronounced in the RPE than in the choroid vessels. Between embryonic day 15 (E15) and E19, we observed a significant increase in the TJ complexity in the RPE, but not in the choroid vessels. The increase coincides with the morphological and functional maturation of the chicken retina suggesting that complex P-face-associated TJs in the RPE are necessary for the formation of an effective blood-retina barrier.

Aging↗
PubMed2002

Gene expression pattern analysis of the tight junction protein, Claudin, in the early morphogenesis of Xenopus embryos.

To study how epithelial layers are formed during early development in Xenopus embryos, we have focused on Claudin, the major component of the tight junction. So far, 19 claudin genes have been found in the mouse, expressed in different epithelial tissues. However, though a number of cytological studies have been done for the roles of Claudins, their expression patterns and functions during early embryogenesis are largely unknown. We found three novel Xenopus claudin genes, which are referred to as claudin-4L1, -4L2, and -7L1. At the early gastrula stage, claudin-4L1, -4L2, and -7L1 mRNAs were detected in the ectoderm and in the mesoderm. At the late gastrula stage, claudin mRNAs were detected in the ectoderm through the involuting archenteron roof. At the neurula stage, claudin-4L1/4L2 and -7L1 mRNAs were differentially expressed in the neural groove and the epidermal ectoderm. At the tailbud stage, the claudin mRNAs were found in the branchial arches, the otic vesicles, the sensorial layer of the epidermis, and along the dorsal midline of the neural tube. In addition, claudin-4L1/4L2 mRNAs were detected in the pronephros and the endoderm, whereas claudin-7L1 mRNA was observed in the epithelial layer of the epidermis.

Amino Acid Sequence↗
PubMed2002

Gene expression pattern analysis of the tight junction protein, Claudin, in the early morphogenesis of Xenopus embryos.

To study how epithelial layers are formed during early development in Xenopus embryos, we have focused on Claudin, the major component of the tight junction. So far, 19 claudin genes have been found in the mouse, expressed in different epithelial tissues. However, though a number of cytological studies have been done for the roles of Claudins, their expression patterns and functions during early embryogenesis are largely unknown. We found three novel Xenopus claudin genes, which are referred to as claudin-4L1, -4L2, and -7L1. At the early gastrula stage, claudin-4L1, -4L2, and -7L1 mRNAs were detected in the ectoderm and in the mesoderm. At the late gastrula stage, claudin mRNAs were detected in the ectoderm through the involuting archenteron roof. At the neurula stage, claudin-4L1/4L2 and -7L1 mRNAs were differentially expressed in the neural groove and the epidermal ectoderm. At the tailbud stage, the claudin mRNAs were found in the branchial arches, the otic vesicles, the sensorial layer of the epidermis, and along the dorsal midline of the neural tube. In addition, claudin-4L1/4L2 mRNAs were detected in the pronephros and the endoderm, whereas claudin-7L1 mRNA was observed in the epithelial layer of the epidermis.

Amino Acid Sequence↗
PubMed1990

Role of calcium in tight junction formation between epithelial cells.

Upon transferring confluent monolayers of Madin-Darby canine kidney (MDCK) cells from a low-Ca2+ medium (1-5 microM) to one with 1.8 mM Ca2+ (Ca switch), tight junctions (TJs) assemble and seal, and transepithelial electrical resistance (TER) develops in 4-5 h, presumably through exocytotic fusion that incorporates junctional components to the surface membrane. In the present work we test this possibility and observe 1) that the Ca switch raises the cytosolic concentration of this ion; 2) that it also increases the membrane area by 22%; 3) that chloroquine, a drug which prevents exocytosis, blocks both the increase of surface membrane and the sealing of TJs; and 4) that if monolayers are not permanently switched to 1.8 mM Ca2+, but are subject to a 15-min pulse, cytosolic free Ca2+ concentration [( Ca2+]c) transiently increases but returns to low values (14 +/- 11 nM) and TER does not develop. Comparisons of the time course of TJ sealing with levels of [Ca2+]c, as well as the relationship between these parameters and extracellular Ca2+ levels, suggest that this ion may act from the extracellular side or in a narrow intracellular domain in the close vicinity of the plasma membrane.

Affinity Labels↗
PubMed1978

Fine structure of tight junctions between rat choroidal cells after osmotic opening induced by urea and sucrose.

After ventriculo-cisternal perfusion of hypertonic urea or sucrose, both the choroid plexus permeability to horseradish peroxidase and the structure of tight junctions between choroidal cells are modified. Intercellular spaces are swollen, continuous ridges are fragmented and intrajunctional spaces are invested by many membranous particles. These morphological alterations appear to be reversible. These ultrastructural data are related to an osmotic maladjustment induced by the introduction of hypertonic solutions into the cerebro-spinal fluid.

Animals↗
PubMed1979

Tight junctions in choroid plexus papillomas.

Four cases of choroid plexus papilloma (CPP) obtained at the time of surgical excision were examined by electron microscopy and compared with normal choroid plexus (CP) of mouse and chick. In apical tight junctions fusion of the two outer leaflets of the adjacent cytoplasmic membrane was verified as in CP. This fact suggests that there is a blood-CSF barrier not only in CP but also in CPP.

Animals↗
PubMed1999

Absence of the tight junctional protein AF-6 disrupts epithelial cell-cell junctions and cell polarity during mouse development.

BACKGROUND: The establishment, maintenance and rearrangement of junctions between epithelial cells are extremely important in many developmental, physiological and pathological processes. AF-6 is a putative Ras effector; it is also a component of tight and adherens junctions, and has been shown to bind both Ras and the tight-junction protein ZO-1. In the mouse, AF-6 is encoded by the Af6 gene. As cell-cell junctions are important in morphogenesis, we generated a null mutation in the murine Af6 locus to test the hypothesis that lack of AF-6 function would cause epithelial abnormalities. RESULTS: Although cell-cell junctions are thought to be important in early embryogenesis, homozygous mutant embryos were morphologically indistinguishable from wild-type embryos through 6.5 days post coitum (dpc) and were able to establish all three germ layers. The earliest morphological abnormalities were observed in the embryonic ectoderm of mutant embryos at 7.5 dpc. The length of the most apical cell-cell junctions was reduced, and basolateral surfaces of those cells were separated by multiple gaps. Cells of the embryonic ectoderm were less polarized as assessed by histological criteria and lateral localization of an apical marker. Mutant embryos died by 10 dpc, probably as a result of placental failure. CONCLUSIONS: AF-6 is a critical regulator of cell-cell junctions during mouse development. The loss of neuroepithelial polarity in mutants is consistent with a loss of efficacy of the cell-cell junctions that have a critical role in establishing apical/basolateral asymmetry.

Animals↗
PubMed1988

Localization of the tight junction protein, ZO-1, is modulated by extracellular calcium and cell-cell contact in Madin-Darby canine kidney epithelial cells.

Using the monoclonal antibody R26.4, we have previously identified a approximately 225-kD peripheral membrane protein, named ZO-1, that is uniquely associated with the tight junction (zonula occludens) in a variety of epithelia including the Madin-Darby canine kidney (MDCK) epithelial cell line (Stevenson, B. R., J. D. Siliciano, M. S. Mooseker, and D. A. Goodenough. 1986. J. Cell Biol. 103:755-766). In this study we have analyzed the effects of cell-cell contact and extracellular calcium on the localization and the solubility of ZO-1. In confluent monolayers under normal calcium conditions, ZO-1 immunoreactivity is found exclusively at the plasma membrane in the region of the junctional complex. If MDCK cells are maintained in spinner culture under low calcium conditions, ZO-1 is diffusely organized within the cytoplasm. After the plating of suspension cells at high cell density in medium with normal calcium concentrations, ZO-1 becomes localized to the plasma membrane at sites of cell-cell contact within 5 h in a process that is independent of de novo protein synthesis. However, if suspension cells are plated at high density in low calcium medium or if suspension cells are plated at low cell density in normal calcium growth medium, ZO-1 remains diffusely organized. ZO-1 localization also becomes diffuse in monolayers that have been established in normal calcium medium and then subsequently switched into low calcium medium. These results suggest that both extracellular calcium and cell-cell contact are necessary for normal localization of ZO-1 to the plasma membrane. An analysis of the solubility properties of ZO-1 from suspension cells and monolayers revealed that high salt, nonionic detergent, and a buffer containing chelators were somewhat more effective at solubilizing ZO-1 from suspension cells than from monolayers.

Antibodies, Monoclonal↗
PubMed2006

Tricellulin is a tight-junction protein necessary for hearing.

The inner ear has fluid-filled compartments of different ionic compositions, including the endolymphatic and perilymphatic spaces of the organ of Corti; the separation from one another by epithelial barriers is required for normal hearing. TRIC encodes tricellulin, a recently discovered tight-junction (TJ) protein that contributes to the structure and function of tricellular contacts of neighboring cells in many epithelial tissues. We show that, in humans, four different recessive mutations of TRIC cause nonsyndromic deafness (DFNB49), a surprisingly limited phenotype, given the widespread tissue distribution of tricellulin in epithelial cells. In the inner ear, tricellulin is concentrated at the tricellular TJs in cochlear and vestibular epithelia, including the structurally complex and extensive junctions between supporting and hair cells. We also demonstrate that there are multiple alternatively spliced isoforms of TRIC in various tissues and that mutations of TRIC associated with hearing loss remove all or most of a conserved region in the cytosolic domain that binds to the cytosolic scaffolding protein ZO-1. A wild-type isoform of tricellulin, which lacks this conserved region, is unaffected by the mutant alleles and is hypothesized to be sufficient for structural and functional integrity of epithelial barriers outside the inner ear.

Alternative Splicing↗
PubMed1979

Absence of tight junctions in endothelium of marrow sinuses: possible significance for marrow cell egress.

The nature of contact between endothelial cells in rat marrow sinuses was studied. Colloidal lanthanum permeated freely into the interendothelial space. Moreover, using freeze-fracture technique, we failed to show junctional structures where these endothelial cells came into contact. With thin sectioning electron microscopy, we observed occasional submembranous densities but the interendothelial distance measured 20 nm and no membrane fusion was seen. Absence of tight junctions between endothelial cells of marrow sinuses may serve a function in marrow cell egress by permitting these cells to slide over each other, thereby changing the luminal size. Within the fixed volume of marrow, an increase in luminal size results in displacement of haemopoietic cells into the lumen.

Animals↗
PubMed2005

HIV-1 gp120 proteins alter tight junction protein expression and brain endothelial cell permeability: implications for the pathogenesis of HIV-associated dementia.

Breakdown of the blood-brain barrier (BBB) is commonly seen in patients with HIV-associated dementia (HAD) despite the lack of productive infection of the brain endothelium. It is likely that secreted viral products play a major role in BBB damage and the development of HAD. The objective of this study is to determine the effects of gp120 proteins on brain endothelial cell permeability and junctional protein expression. Our results showed that treatment of cultured human brain endothelial cells with gp120 for 24 hours results in increased permeability of the endothelial monolayer. Also, gp120 proteins caused disruption and downregulation of the tight junction proteins ZO-1, ZO-2, and occludin in these cells. Other junctional proteins such as claudin-1 and claudin-5 were unaffected by gp120 treatment. These data demonstrate that HIV gp120 proteins alter both the functional and molecular properties of the BBB, which could increase trafficking of HIV, infected cells, and toxic humoral factors into the central nervous system and contribute to the pathogenesis of HAD.

Analysis of Variance↗
PubMed1986

Morphology of tight junctions in the ciliary epithelium of rabbits during arachidonic acid-induced breakdown of the blood-aqueous barrier.

A reversible breakdown of the blood-aqueous barrier in the iridial processes of rabbits has been induced by arachidonic acid as demonstrated by the passage of horseradish peroxidase at places through the tight junctions. Freeze-fracture images reveal very discontinuous P-face ridges. However, the analysis of complementary replicas demonstrates that discontinuities of P-face ridges are always complemented by particles or short bars found in the E-face furrows. Though the problem exists of correlating freeze-fracture images of the junctional structure to the focal passage of horseradish peroxidase, the data suggest that the discontinuities of P-face ridges cannot be the structural counterpart of the passage of horseradish peroxidase. Alternative pathways of horseradish peroxidase are discussed in context with the offset bifibrillary model of the junction.

Animals↗
PubMed1979

Opening of tight junctions in cerebral endothelium. I. Effect of hyperosmolar mannitol infused through the internal carotid artery.

Infusion of 1.8 M mannitol solution into the internal carotid artery of Wistar rats allows horseradish peroxidase (HRP) to cross cerebral vascular endothelium via intercellular pathways. This was made evident by density gradients of HRP observed in consecutive tight junctional compartments following in vivo administration, and by the passage of colloidal lanthanum through junctional membrane appositions of glutaraldehyde fixed cerebral endothelium. Three hours after mannitol infusion, small non-capillary vascular segments were still focally permeable to HRP. Twenty-four hours after the osmotic insult, the tracer was absent in the affected hemisphere. Water and electrolyte assays indicated absence of brain edema during the period of observation of blood-brain barrier opening.

Animals↗
PubMed2005

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats.

Increased intestinal permeability has been observed in numerous human autoimmune diseases, including type-1 diabetes (T1D) and its' animal model, the BB-wor diabetic prone rat. We have recently described zonulin, a protein that regulates intercellular tight junctions. The objective of this study was to establish whether zonulin-dependent increased intestinal permeability plays a role in the pathogenesis of T1D. In the BB diabetic-prone rat model of T1D, intestinal intraluminal zonulin levels were elevated 35-fold compared to control BB diabetic-resistant rats. Zonulin up-regulation was coincident with decreased small intestinal transepithelial electrical resistance, and was followed by the production of autoantibodies against pancreatic beta cells, which preceded the onset of clinically evident T1D by approximately 25 days. In those diabetic prone rats that did not progress to diabetes, both intraluminal zonulin and transepithelial electrical resistance were similar to those detected in diabetic-resistant animal controls. Blockade of the zonulin receptor reduced the cumulative incidence of T1D by 70%, despite the persistence of intraluminal zonulin up-regulation. Moreover, treatment responders did not seroconvert to islet cell antibodies. Combined together, these findings suggest that the zonulin-induced loss in small intestinal barrier function is involved in the pathogenesis of T1D in the BB diabetic-prone animal model.

Animals↗
PubMed1981

Correlation between radionuclides uptake and ultrastructural features of tight junctions in the capillary wall of meningiomas.

The uptake of Tc-99m pertechnetate and Co-57 bleomycin and the ultrastructure of small blood vessels were studied in 10 cases of meningioma. When thin sections of 120 contact areas between adjacent endothelial cells were examined, 92% of the intercellular contacts contained one to three punctate tight junctions. Freeze fracture preparations revealed fascia occludens with one to four sealing strands. These findings are consistent with the high permeability the meningiomas displayed for both of the radiopharmaceuticals.

Capillaries↗
PubMed1999

Tight junction protein ZO-2 is differentially expressed in normal pancreatic ducts compared to human pancreatic adenocarcinoma.

Differential display of hamster mRNA identified a fragment present in normal pancreatic duct cells that is not expressed in pancreatic duct carcinoma cells. Sequence analysis showed an 88% and 82% identity, respectively, to the cDNA of the canine and human tight junction zo-2 gene. Semi-quantitative RT-PCR analysis of human ZO-2 revealed a striking difference in the expression of various regions of the ZO-2 transcript in normal and neoplastic cells and the presence of an abnormality at the 5'-end of mRNA. RACE analysis identified 2 human ZO-2 mRNAs that encode proteins of different lengths, designated as ZO-2A and ZO-2C. The difference between the 2 forms of ZO-2 is the absence of 23 amino acid residues at the N terminus of ZO-2C compared with ZO-2A. Although ZO-2C was expressed in normal pancreatic cells and a majority of neoplastic tissues analyzed, ZO-2A was undetectable except in one case in all of the pancreatic adenocarcinomas analyzed. This suggests the presence of a yet to be identified motif important for cell-growth regulation within the 23-amino acid residue N-terminal peptide of ZO-2A, MPVRGDRGFPPRRELSGWLRAPG.

Adenocarcinoma↗
PubMed1990

Decreased hepatocellular volume and intact morphology of tight junctions in calcium deprivation-induced cholestasis. Stereological and multiple indicator dilution analysis.

Cholestasis induced by perfusion of the liver with hypocalcemic media has been ascribed to several defects in bile secretion including increased biliary permeability. To investigate this model of cholestasis further, livers perfused with hypo- and normocalcemic media were examined stereologically using thin sections and freeze-fracture replicas. Organization of tight junctions was not altered by hypocalcemia; neither the number of strands nor the junctional depth were significantly affected. By contrast, the volume of hepatocytes decreased by 11% (p less than 0.001), compensated for by an increase in the space of Dissé and of the sinusoids. The canalicular length decreased by 25% (p less than 0.01), while the canalicular membrane surface was not altered. Multiple indicator dilution studies confirmed a decrease in hepatocellular volume, measured as the water space by 14% (p less than 0.03). This was compensated for by an increase in the extravascular sucrose, but not the albumin space. Immediately after switching from normo- to hypocalcemic perfusate a K+ efflux of 62 mumol/g liver was observed corresponding to approx. 8% of the hepatocellular water space. Our results suggest that hypocalcemia-induced cholestasis is due, at least in part, to a disturbance of the osmotic equilibrium, possibly caused by impairment of an ion transport system involved in hepatocellular volume control.

Animals↗