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PubMed2004

The tight junction: a multifunctional complex.

Multicellular organisms are separated from the external environment by a layer of epithelial cells whose integrity is maintained by intercellular junctional complexes composed of tight junctions, adherens junctions, and desmosomes, whereas gap junctions provide for intercellular communication. The aim of this review is to present an updated overview of recent developments in the area of tight junction biology. In a relatively short time, our knowledge of the tight junction has evolved from a relatively simple view of it being a permeability barrier in the paracellular space and a fence in the plane of the plasma membrane to one of it acting as a multicomponent, multifunctional complex that is involved in regulating numerous and diverse cell functions. A group of integral membrane proteins-occludin, claudins, and junction adhesion molecules-interact with an increasingly complex array of tight junction plaque proteins not only to regulate paracellular solute and water flux but also to integrate such diverse processes as gene transcription, tumor suppression, cell proliferation, and cell polarity.

Animals↗
PubMed1987

Intestinal absorptive cell tight junctions are linked to cytoskeleton.

Permeation of intercellular tight junctions in epithelia may be altered by maneuvers that affect the cytoskeleton. Conversely, agents that alter tight-junction permeability also often produce alterations in cytoskeletal structure. However, anatomic links between the tight junction and the cytoskeleton have not been clearly defined. We explore the anatomy of the perijunctional cytoskeleton by applying electron microscopy to cytoskeletal preparations of whole intestinal absorptive cells using detergent extraction techniques. Individual elements of the perijunctional cytoskeleton, including actin microfilaments as determined by S1 labeling, appear to associate with the tight junction by means of plaque-like densities that intimately associate with the lateral membrane at the site of the tight junction. Furthermore, such associations are not diffuse within the tight junction, but occur only at sites of fusions ("kisses") between lateral membranes that are thought to represent the specific intrajunctional sites at which the barriers to transjunctional permeation reside. These data provide evidence of intimate cytoskeletal-tight-junction associations, which may represent the anatomical basis for cytoskeletal control of tight-junction permeability.

Absorption↗
PubMed1998

Elevated plasma cortisol reduces permeability of mammary tight junctions in the lactating bovine mammary epithelium.

Induction of tight junction permeability in the mammary epithelium decreases milk secretion, and in cows tight junctions become leaky after 17 h of milk accumulation. In vitro studies demonstrate the importance of glucocorticoids for the formation and maintenance of tight junctions. In this study we examined whether cortisol can prevent mammary tight junction permeability in the lactating gland in vivo, and inhibit the associated milk loss, using our milk-accumulation model to challenge tight junction patency. Following a 4-day control period Jersey cows were subjected to a 24-h period in which they were milked twice at 0700 and 1500 h (TM;n=6), once at 0700 h (OM;n=7), or once and treated with ACTH (40 IU per 2 h, starting after 14 h of milk accumulation) to increase endogenous cortisol levels (OM+ACTH;n=7). Frequent blood samples for cortisol, lactose and glucose analyses were taken via indwelling jugular catheters. ACTH treatment resulted in a sustained elevation of systemic cortisol concentrations. Plasma lactose, an indicator of tight junction leakiness, was not changed in TM cows, but began to increase rapidly at 17 h of milk accumulation in OM cows. Treatment with ACTH prevented the increase in plasma lactose, although levels were slightly, but not significantly, higher than in TM cows, indicating that elevated plasma cortisol reduced mammary tight junction leakiness. Milk yield was reduced by 12% in both once-milked groups, despite cortisol preventing tight junction leakiness. However, the milk loss in the latter group may not be related to leaky tight junctions, but be due to a reduction in milk precursor uptake by the mammary gland. Consistent with this notion was a 34% increase in plasma glucose levels in OM+ACTH cows only.

Adrenocorticotropic Hormone↗
PubMed1980

Qualitative and quantitative freeze-fracture studies on olfactory and nasal respiratory epithelial surfaces of frog, ox, rat, and dog. III. Tight-junctions.

A comparison of the tight-junctions of various cell types in the nasal epithelia of frog, ox, rat and dog shows that Bowman's gland cells have lowest number of strands (4-8), whereas olfactory receptor and supporting, and ciliated respiratory cells show no conspicuous differences and have 6-11 strands. Tight-junctional strand numbers show slight species-dependent variations. In regions where three cells join (observed for receptor and respiratory cells), fracture faces show two parallel strands which fuse at certain points. These strands run perpendicularly to the rest of the tight-junctional belt, which also shows an increased number of strands (13-16) in this region. Tight-junctions of mammalian olfactory dendritic endings usually show strands composed of particles, whereas those of the other three epithelial cell types consist of continuous or discontinuous bars. Tight-junctions of dendritic endings of the frog also conform to the latter type. Differences in strand density are only slight and range from 16-27 strands/microns. Small angular gap-junctions were observed only within the tight-juctions of supporting cells in the rat.

Animals↗
PubMed2003

JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1.

MAGI-1 is a membrane-associated guanylate kinase protein at tight junctions in epithelial cells. It interacts with various molecules and functions as a scaffold protein at cell junctions. We report here a novel MAGI-1-binding protein that we named junctional adhesion molecule 4 (JAM4). JAM4 belongs to an immunoglobulin protein family. JAM4 was colocalized with ZO-1 in kidney glomeruli and in intestinal epithelial cells. Biochemical in vitro studies revealed that JAM4 bound to MAGI-1 but not to ZO-1, whereas JAM1 did not bind to MAGI-1. JAM4 and MAGI-1 interacted with each other and formed clusters in COS-7 cells when coexpressed. JAM4 mediated calcium-independent homophilic adhesion and was accumulated at cell-cell contacts when expressed in L cells. MAGI-1, ZO-1, and occludin were recruited to JAM4-based cell contacts. JAM4 also reduced the permeability of CHO cell monolayers. MAGI-1 strengthened JAM4-mediated cell adhesion in L cells and sealing effects in CHO cells. These findings suggest that JAM4 together with MAGI-1 provides an adhesion machinery at tight junctions, which may regulate the permeability of kidney glomerulus and small intestinal epithelial cells.

Adenoviridae↗
PubMed2004

Disruption of the cingulin gene does not prevent tight junction formation but alters gene expression.

Cingulin, a component of vertebrate tight junctions, contains a head domain that controls its junctional recruitment and protein interactions. To determine whether lack of junctional cingulin affects tight-junction organization and function, we examined the phenotype of embryoid bodies derived from embryonic stem cells carrying one or two alleles of cingulin with a targeted deletion of the exon coding for most of the predicted head domain. In homozygous (-/-) embryoid bodies, no full-length cingulin was detected by immunoblotting and no junctional labeling was detected by immunofluorescence. In hetero- and homozygous (+/- and -/-) embryoid bodies, immunoblotting revealed a Triton-soluble, truncated form of cingulin, increased levels of the tight junction proteins ZO-2, occludin, claudin-6 and Lfc, and decreased levels of ZO-1. The +/- and -/- embryoid bodies contained epithelial cells with normal tight junctions, as determined by freeze-fracture and transmission electron microscopy, and a biotin permeability assay. The localization of ZO-1, occludin and claudin-6 appeared normal in mutant epithelial cells, indicating that cingulin is not required for their junctional recruitment. Real-time quantitative reverse-transcription PCR (real-time qRT-PCR) showed that differentiation of embryonic stem cells into embryoid bodies was associated with up-regulation of mRNAs for several tight junction proteins. Microarray analysis and real-time qRT-PCR showed that cingulin mutation caused a further increase in the transcript levels of occludin, claudin-2, claudin-6 and claudin-7, which were probably due to an increase in expression of GATA-6, GATA-4 and HNF-4alpha, transcription factors implicated in endodermal differentiation. Thus, lack of junctional cingulin does not prevent tight-junction formation, but gene expression and tight junction protein levels are altered by the cingulin mutation.

Animals↗
PubMed2000

Assembly of tight junctions during early vertebrate development.

Tight junction formation during development is critical for embryonic patterning and organization. We consider mechanisms of junction biogenesis in cleaving mouse and Xenopus eggs. Junction assembly follows the establishment of cell polarity at 8-cell (mouse) or 2-cell (Xenopus) stages, characterized by sequential membrane delivery of constituents, coordinated by embryonic (mouse) or maternal (Xenopus) expression programmes. Cadherin adhesion is permissive for tight junction construction only in the mouse. Occludin post-translational modification and membrane delivery, mediated by delayed ZO-1 alpha(+)isoform expression in the mouse, provides a mechanism for completion of tight junction biogenesis and sealing, regulating the timing of blastocoel cavitation.

Animals↗
PubMed2006

Tight junctions: molecular architecture and function.

Tight junctions are the most apical component of the epithelial junctional complex and are crucial for the formation and functioning of epithelial and endothelial barriers. They regulate selective diffusion of ions and solutes along the paracellular pathway and restrict apical/basolateral intramembrane diffusion of lipids. Research over the past years provided much insight into the molecular composition of tight junctions, and we are starting to understand the mechanisms that permit selective paracellular diffusion. Moreover, a complex network of proteins has been identified at tight junctions that is based on cytoskeleton-linked adaptors that recruit and thereby often regulate different types of signaling components that regulate epithelial proliferation, differentiation, and polarization.

Animals↗
PubMed2005

Rnd3/RhoE induces tight junction formation in mammary epithelial tumor cells.

Glucocorticoid hormones stimulate adherens and tight junction formation in Con8 mammary epithelial tumor cells through a multistep process in which the membrane organization of structural apical junction proteins and tight junction sealing is controlled by specific signal transduction components. We have previously shown that dexamethasone stimulation of apical junction formation requires down-regulation of the small GTPase RhoA. Here we identified Rnd3/RhoE, a GTPase-deficient Rho family member and RhoA antagonist, as a key regulator of apical junction dynamics. Exogenously expressed Rnd3/RhoE co-localized with actin at the cell periphery and induced the localization of the adherens junction protein beta-catenin and the tight junction protein ZO-1 to sites of cell-cell contact, and led to the formation of highly sealed tight junctions. Treatment with glucocorticoids was not required to achieve complete apical junction remodeling. Consistent with Rnd3/RhoE acting as an antagonist of RhoA, expression of Rnd3/RhoE rescued the disruptive effects of constitutively active RhoA on apical junction organization. Our results demonstrate a new role for the Rho family member Rnd3/RhoE in regulating the assembly of the apical junction complex and tight junction sealing.

Animals↗
PubMed2001

Altered expression of occludin and tight junction formation in psoriasis.

In simple epithelia, tight junctions are well developed and have barrier and fence functions. On the other hand, tight junctions are less developed in stratified epithelia. In the rodent epidermis, only maculae occludentes (i.e. focal strands or spot tight junctions) are observed in the most superficial zone of the granular cell layer. Occludin is an integral membrane protein, and is localized at tight junctions in simple epithelia. In normal epidermis, occludin is expressed at the maculae occludentes in the granular cell layer, indicating that it is associated with keratinocyte differentiation. Thus, we examined occludin expression in psoriasis, in which differentiation of keratinocytes is impaired. In psoriasis, occludin was expressed more broadly in the upper epidermis than in normal epidermis. In addition, immunoelectron microscopy showed occludin to be concentrated on the maculae occludentes in the spinous layer of psoriatic skin. These findings indicate that occludin and the formation of tight junctions are related to the proliferation and differentiation of keratinocytes, and to the pathogenesis of psoriasis.

Adult↗
PubMed1999

Occludin and claudins in tight-junction strands: leading or supporting players?

Tight junctions have attracted much interest from cell biologists, especially electron microscopists, since on freeze-fracture electron microscopy they appear as a well-developed network of continuous, anastomosing intramembranous strands (tight-junction strands). These strands might be directly involved in the 'barrier' as well as 'fence' functions in epithelial and endothelial cell sheets, but until recently little was known of their constituents. This review discusses current understanding of the molecular architecture of tight-junction strands, focusing on the recent discovery of two distinct types of tight-junction-specific integral membrane proteins, occludin and claudins.

Animals↗
PubMed2000

Enhancing paracellular permeability by modulating epithelial tight junctions.

The intestinal epithelium is a major barrier to the absorption of hydrophilic drugs. The presence of intercellular junctional complexes, particularly the tight junctions (zona occludens), renders the epithelium impervious to hydrophilic drugs, which cannot diffuse across the cells through the lipid bilayer of the cell membranes. There have been significant advances in understanding the structure and cellular regulation of tight junctions over the past decade. This article reviews current knowledge regarding the physiological regulation of tight junctions and paracellular permeability, and recent progress towards the rational design of agents that can effectively and safely increase paracellular permeability via modulation of tight junctions.

Journal Article↗
PubMed2001

Tight junctions and their role in cancer metastasis.

Tight Junctions govern the permeability of endothelial and epithelial cells and are the most topical structures of these cell types. Tight junctions create an intercellular barrier and intramembrane diffusion fence. An important step in the formation of cancer metastases interaction and penetration of the vascular endothelium by dissociated cancer cells. Early studies demonstrated a correlation between the reduction of tight junctions and tumour differentiation and experimental evidence has emerged to place tight junctions in the frontline as the structure that cancer cells must overcome in order to metastasise. Changes in tight junction function are thus an early and key aspect in cancer metastasis. Further work is required to fully realise the potential that this structure has in cancer invasion and metastasis in order to develop new and novel therapies in the prevention of tumour metastasis.

Animals↗
PubMed2001

Pilt, a novel peripheral membrane protein at tight junctions in epithelial cells.

Tight junctions (TJs) serve as a barrier that prevents solutes and water from passing through the paracellular pathway, and as a fence between the apical and basolateral plasma membranes in epithelial cells. TJs consist of transmembrane proteins (claudin, occludin, and JAM) and many peripheral membrane proteins, including actin filament (F-actin)-binding scaffold proteins (ZO-1, -2, and -3), non-F-actin-binding scaffold proteins (MAGI-1), and cell polarity molecules (ASIP/PAR-3 and PAR-6). We identified here a novel peripheral membrane protein at TJs from a human cDNA library and named it Pilt (for protein incorporated later into TJs), because it was incorporated into TJs later after the claudin-based junctional strands were formed. Pilt consists of 547 amino acids with a calculated M(r) of 60,704. Pilt has a proline-rich domain. In cadherin-deficient L cells stably expressing claudin or JAM, Pilt was not recruited to claudin-based or JAM-based cell-cell contact sites, suggesting that Pilt does not directly interact with claudin or JAM. The present results indicate that Pilt is a novel component of TJs.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Na-K-ATPase regulates tight junction permeability through occludin phosphorylation in pancreatic epithelial cells.

Tight junctions are crucial for maintaining the polarity and vectorial transport functions of epithelial cells. We and others have shown that Na-K-ATPase plays a key role in the organization and permeability of tight junctions in mammalian cells and analogous septate junctions in Drosophila. However, the mechanism by which Na-K-ATPase modulates tight junctions is not known. In this study, using a well-differentiated human pancreatic epithelial cell line HPAF-II, we demonstrate that Na-K-ATPase is present at the apical junctions and forms a complex with protein phosphatase-2A, a protein known to be present at tight junctions. Inhibition of Na-K-ATPase ion transport function reduced protein phosphatase-2A activity, hyperphosphorylated occludin, induced rearrangement of tight junction strands, and increased permeability of tight junctions to ionic and nonionic solutes. These data suggest that Na-K-ATPase is required for controlling the tight junction gate function.

Cadherins↗
PubMed1988

Tight-junctional strands first appear in regions where three cells meet in differentiating olfactory epithelium: a freeze-fracture study.

Tight junctions of the olfactory epithelium of rat embryos were studied at the 14th day of gestation and during their subsequent development. Two different epithelial morphologies could be distinguished at the 14th gestational day. In one group of embryos the epithelial surface appeared undifferentiated, with tight-junctional strands found exclusively in regions where three cells met. The main orientation of these strands is in a direction parallel to the longitudinal orientation of the epithelial cells. These junctions resemble tight junctions that interconnect three cells, i.e. tricellular tight junctions, in that respect. However, unlike these the junctions mainly have single strands of particles, whereas tricellular junctions usually consist of paired strands of particles. Tight-junctional strands were completely absent in areas where two cells met. These areas, i.e. those of incipient bicellular tight junctions, had gap-junction-like aggregates of intramembranous particles. Another group of 14-day-old embryos displayed a differentiating olfactory epithelial surface with bicellular as well as tricellular tight-junctional strands. The latter ones were paired. Here too the tight-junctional belts displayed some gap-junction-like aggregates of particles, but there were considerably fewer of these than earlier. As one or the other tight-junctional appearance was always seen in a single freeze-fracture replica, it is reasonable to assume that the two tight-junctional appearances reflect a sequential pattern of differentiation peculiar to the whole surface of the olfactory epithelium, i.e. to surfaces of receptor cells as well as to surfaces of supporting cells. It would appear that, at the onset of olfactory epithelial differentiation, tight junctions first interconnect cells in regions where three cells meet and that tricellular strand formation precedes the formation of bicellular strands. When strands were present at the 14th day of embryonic development, their numbers were lower than those found later. However, strand packing, expressed as the density per micrometre of strands parallel to the epithelial surface, increased beginning at the 16th day of embryonic development.

Animals↗
PubMed1989

Filipin-induced deformations in plasma membranes of cultured bovine corneal endothelial cells with incomplete belts of tight junctions.

Complete belts of intact tight junctions are thought to act as barriers to the movement of cholesterol in the plane of the plasma membrane. As cholesterol can be revealed by filipin-induced membrane deformations on freeze-fracture images, we studied the distribution of these deformation in cultured bovine corneal endothelial cells with incomplete belts of tight junctions. While the extent of filipin-induced deformations differed between individual cells, there is a homogeneous distribution of filipin-induced deformations on both sides of the incomplete junctional belt of endothelial cells. Our results suggest that cultured endothelial cells do not polarize cholesterol, possibly because of the incomplete tight-junctional barrier.

Animals↗
PubMed2000

Modulation of tight junction structure and function by cytokines.

Dynamic regulation of tight junction function is fundamental to many physiologic processes. Disruption of tight junction function drastically alters paracellular permeability and is a hallmark of many pathologic states. Recently, an increasing number of cytokines have been shown to influence tight junction function both in vitro and in vivo. Cytokine-induced effects on tight junction barrier function have also been correlated with effects on intrinsic tight junction proteins and the associated actin cytoskeleton. The aim of this article is to review studies relating to the effects of cytokines on tight junction function and structure.

Animals↗