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Normaltight junctions also contain a second major transmembrane protein calledoccludin, but the function of this protein is uncertain, and it does not seem tobe as essential as the claudins. A third transmembrane protein, tricellulin(related to occludin), is required to seal cell membranes together and preventtransepithelial leakage at the points where three cells meet.The claudin protein family has many members (24 in humans), and theseare expressedin different combinations in different epithelia to confer particular permeability properties on the epithelial sheet. They are thought to formparacellular pores-selective channels allowing specific ions to cross the tightjunctional barrier, from one extracellular space to another. A specific claudinfound in kidney epithelial cells, for example, is needed to let MgZ* pass betweenthe cells of the sheet so that this ion can be resorbed from the urine into theblood.
A mutation in the gene encoding this claudin results in excessiveloss ofMgZ* in the urine.Playa KeyPartin theScaffoldProteinsin JunctionalComplexesControlof CellProliferationThe claudins and occludins have to be held in the right position in the cell, so asto form the tight-junctional network of sealing strands.This network usually liesjust apical to the adherens and desmosome junctions that bond the cellstogether mechanically, and the whole assembly is called a iunctional complex(Figure 19-27).
The parts of this junctional complex depend on each other forFigure 19-26 A model of a tight junction.(A)Thesealingstrandshold adjacentplasmamembranestogether.Thestrandsproteinsarecomposedof transmembranethat makecontactacrossthe intercellularspaceand createa seal.(B)The molecularcompositionof a sealingstrand.Theclaudinsarethe mainfunctionalthe roleof the occludinscomponents;is uncertain.1154Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixa c t i ni n m i c r o v i l l iFigure19-27 A junctionalcomplexbetweentwo epithelialcellsin thelining of the gut.
Mostapically,thereis atightjunction;beneaththis,an adherensjunction;and beneaththe adherensjunction,a desmosomaljunction.Thisexampleis from a vertebrate;in insects,the arrangementis different.(CourtesyofDanielS.Friend.)tight junction(claudins)a d h e r e n sj u n c t i o n(cadherins)d e s m o s o m aj ul n c t i o n(cadherins)k e r a t i nf i l a m e n t stheir formation. For example, anti-cadherin antibodies that block the formationof adherens junctions also block the formation of tight junctions. The positioning and organization of tight junctions in relation to these other structures isthought to depend on association with intracellular scaffold proteins of the Tjp(Tight junction protein) family, also called ZO proteins (a tight junction is alsoknown as a zonula occludens).The vertebrate Tjp proteins belong to the samefamily as the Discs-large proteins that we mentioned earlier for their role atsynapses, and they anchor the tight-junctional strands to other componentsincluding the actin cytoskeleton.In invertebrates such as insects and mollusks, occluding junctions have adifferent appearance and are called septate junctions.
Like tight junctions,these form a continuous band around each epithelial cell, but the structure ismore regular, and the interacting plasma membranes are joined by proteins thatare arranged in parallel rows with a regular periodicity (Figure lg-28). septatejunctions are nevertheless based on proteins homologous to the vertebrateclaudins, and they depend on scaffold proteins in a similar way, including inparticular the same Discs-large protein that is present at synapses.Mutant fliesthat are deficient in Discs-largehave defective septatejunctions.Strikingly, these mutants also develop epithelial tumors, in the form of largeovergrowths of the imaginal discs-the structures in the fly larva from whichmost of the adult body derives (as described in chapter 22).
The gene takes itsname from this remarkable effect, which depends on the presence of bindingsites for growth regulators on the Discs-largeprotein. But why should the apparatus of cell-cell adhesion be linked in this way with the control of cell proliferation? The relationship seems to be fundamental: in vertebrates also, genes_].",,,Figure19-28A septatejunction.A conventionalelectronmicrographof aseptatejunctionbetweentwo epithelialcellsin a mollusk.The interactingplasmamembranes,seenin crosssection,areconnectedby parallelrowsofjunctionalproteins.The rows,which havea regularperiodicity,are seenas densebars,orsepta.(FromN.B.Gilula,in CellCommunicationCox,ed.],pp.
1-29.[R.P.NewYork:Wilev,1974.)l-,TIGHTJUNCTIONSAND THEORGANIZATIONOF EPITHELIA1155homologous to Discs largehave this dual involvement. One possibility is that itreflects a basic mechanism for repair and maintenance of epithelia. If anepithelial cell is deprived of adhesive contacts with neighbors, its program ofgrowth and proliferation is activated, thereby creating new cells to reconstructa continuous multicellular sheet.
In fact, a large body of evidence indicates thatjunctional complexes are important sites of cell-cell signaling not only viaDiscs-large but also through other components of these structures, includingcadherins as we have seen.Cell-CellJunctionsand the BasalLaminaGovernApico-BasalPolarityin EpitheliaMost cells in animal tissues are strongly polarized: they have a front that differsfrom the back, or a top that differs from the bottom.
Examples include virtuallyall epithelial cells, as we have discussed, as well as neurons with their dendrite-axon polarity, migrating fibroblasts and white blood cells, with their locomotor Ieading edge and trailing rear end, and many other cells in embryos asthey prepare to divide asymmetrically to create daughter cells that are different.A core set of components is critical for cell polarity in all these cases,throughoutthe animal kingdom, from worms and flies to mammals.In the case of epithelial cells, these fundamental generators of cell polarityhave to establishthe difference between the apical and basal poles, and they haveto do so in a properly oriented way, in accordance with the cell's surroundings.The basic phenomenon is nicely illustrated by experiments with a cultured lineof epithelial cells, called MDCK cells (Figure f 9-29A).
These can be separatedfrom one another and cultured in suspension in a collagen gel. A single isolatedcell in these circumstancesdoes not show any obvious polarity, but if it is allowedto divide to form a small colony of cells,these cells will organize themselvesintoa hollow epithelial vesiclewhere the polarity of each cell is clearly apparent.
Thevesiclebecomes surrounded by a basal lamina, and all the cells orient themselvesin the same way, with apex-specific marker molecules facing the lumen. Evidently, the MDCK cells have a spontaneous tendency to become polarized, butthe mechanism is cooperative and depends on contacts with neighbors.To discover how the underlying molecular mechanism works, the first stepis to identify its components. Studies in the worm C. elegansand in Drosophilahave been most informative here.
In the worm, a screen for mutations upsettingthe organization of the early embryo has revealeda set of genesessentialfor normal cell polarity and asymmetry of cell division (as discussed in Chapter 22).There are at least six ofthese genes, called Par (partitioning defectiue)genes.Inall animal speciesstudied, they and their homologs (along with other genes discovered through studies in Drosophila and vertebrates)have a fundamental rolenot just in as),rynmetriccell division in the early embryo, but in many other processesof cell polarization, including the polarization of epithelial cells.The Par4gene of C.
elegans,for example, is homologous to a gene calledLkbl in mammalsand Drosophila, coding for a serine/threonine kinase. In the fly, mutations ofAPICAL-BASALPOLARITYAPICAL-BASALPOLARITYAPICAL-BASALPOLARIWGolgiaminin nucleus tight junction( A ) N O R M A LC E L LC L U S T E R( B ) R A CF U N C T I O BNL O C K E D( C ) R A CF U N C T I O BNL O C K E DP L U SE X O G E N O ULSA M I N I NFigure19-29 Cooperativepolarizationofa clusterof epithelialcellsin cultureandits dependenceon Racand laminin.Cellsof the MDCKline,derivedfrom dog kidneyembeddedepithelium,weredissociated,in a collagenmatrix,and allowedtoproliferate,creatingsmallisolatedinshownhereschematicallycolonies,crosssection.(A)Thecellsin sucha colonywill normallyorganizethemselvesinto an epitheliumspontaneouslysurroundinga centralcavity.StainingforZO1actin(whichmarksapicalmicrovilli),protein(a tight-junctionprotein),Golgiand laminin(a basallaminaapparatus,component)showsthat the cellshaveallwithbecomepolarized,cooperativelyapicalcomponentsfacingthe lumenofthe cavityand basalcomponentsfacingthe surroundingcollagengel.(B)Whenof aRacfunctionis blockedby expressionform of the protein,dominant-negativethe cellsshow invertedpolarity,failtoform a cystwith a centralcavity,and ceaseto depositlamininin the normalmanneraroundthe peripheryof the cellcluster.(C)Whenthe cystis embeddedin a matrixrichin exogenouslaminin,near-normalpolarityis restoredeventhough Racfunctionis stillblocked.(BasedonL.E.O'Brienet al.,Not CellBiol.3:831-838,from Macmillan2001.With oermissionLtd.)Publishers1156Chapter19:CellJunctions,MatrixCellAdhesion,and the Extracellular(A) NON-POLARIZECDELL(B)P O L A R I Z ECDE L La c t i n - ifl l e d m i c r o v i l l iL K B l1i n a c t i v eL K B 1a c t i v eir_;this gene disrupt the polarity of the egg cell and of cells in epithelia.
In humans,such mutations give rise to Peutz-Jegherssyndrome, involving disorderly abnormal growths of the lining of the gut and a predisposition to certain rare types ofcancer. \A/hen cultured human colon epithelial cells are prevented from expressing LKBl, they fail to polarize normally. Moreover, when such cells in culture areartificially driven to express abnormally high levels of LKBI activity, they canbecome individually polarized, even when isolated from other cells, and surrounded on all sides by a uniform medium (Figure f9-30).
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