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In fact, more than 60% of the cell types in the vertebratebody are epithelial. Just as cell membranes enclose and partition the interior ofthe eucaryotic cell, so epithelia enclose and partition the animal body, lining allits surfacesand cavities, and creating internal compartments where specializedprocessesoccur. The epithelial sheet seems to be one of the inventions that lieat the origin of animal evolution, diversifying in a huge variety of ways (aswe seein chapter 23), but retaining an organization based on a set of conserved molecular mechanisms that practically all epithelia have in common.Essentially all epithelia are anchored to other tissue on one side-the basalside-and free of such attachment on their opposite side-the apical side.
Abasal lamina lies at the interface with the underlying tissue, mediating theattachment, while the apical surface of the epithelium is generally bathed byextracellular fluid (but sometimes covered by material that the cells havesecretedat their apices).Thus all epithelia are structurally polarized, and so aretheir individual cells: the basal end of a cell, adherent to the basal lamina belowdiffers from the apical end, exposed to the medium above.correspondingly, all epithelia have at least one function in common: theyserve as selective permeability barriers, separating the fluid that permeates thetissue on their basal side from fluid with a different chemical composition ontheir apical side. This barrier function requires that the adjacent cells be sealedtogether by occluding junctions, so that molecules cannot leak freely acrossthecell sheet.
In this section we consider how the occluding junctions are formed,and how the polarized architecture of the epithelium is maintained. These twofundamental aspectsof epithelia are closely linked: the junctions play a key partin organizing and maintaining the polarity of the cells in the sheet.TightJunctionsForma SealBetweenCellsand a FenceBetweenMembraneD o ma i n sThe occluding junctions found in vertebrate epithelia are called tight junctions.The epithelium of the small intestine provides a good illustration of their structure and function (see Figure rg-3).
This epithelium has a simple columnarstructure; that is, it consists of a single layer of tall (columnar) cells.These are ofT1GHTJUNCTIONSAND THE',ORGAN|ZAT|ONOF EPITHELIA.,.:.'i.:,lr',,'''.i'1''5.!several differentiated types, but the majority are absorptive cells, specialized foruptake of nutrients from the internal cavity, or lumen, of the gut.The absorptive cells have to transport selected nutrients across the epithelium from the lumen into the extracellular fluid that permeates the connectivetissue on the other side.
From there, these nutrients diffuse into small blood vessels to provide nourishment to the organism. This transcellular transportdepends on two sets of transport proteins in the plasma membrane of theabsorptive cell. One set is confined to the apical surface of the cell (facing thelumen) and actively transports selectedmolecules into the cell from the gut.
Theother set is confined to the basolateral (basal and lateral) surfaces of the cell, andit allows the same molecules to leave the cell by facilitated diffusion into theextracellular fluid on the other side of the epithelium. For this transport activityto be effective,the spacesbetween the epithelial cells must be tightly sealed,sothat the transported molecules cannot leak back into the gut lumen throughthese spaces (Figure f9-23). Moreover, the proteins that form the pumps andchannels must be correctly distributed in the cell membranes: the apical set ofactive transport proteins must be delivered to the cell apex (as discussed inChapter 13) and must not be allowed to drift to the basolateral surface, and thebasolateral set of channel proteins must be delivered to the basolateral surfaceand must not be allowed to drift to the apical surface.
The tight junctionsbetween epithelial cells, besides sealing the gaps between the cells, may alsofunction as "fences" helping to separatedomains within the plasma membraneof each cell, so as to hinder apical proteins (and lipids) from diffusing into thebasal region, and vice versa (seeFigure 19-23).The sealing function of tight junctions is easyto demonstrate experimentally:a low-molecular-weight tracer added to one side of an epithelium will generallynot passbeyond the tight junction (Figure lS-24).This seal is not absolute,however.Although all tight junctions are impermeable to macromolecules,their permeability to small molecules varies. Tight junctions in the epithelium lining thesmall intestine, for example, are 10,000times more permeable to inorganic ions,Na ' - d r i v e nglucose symportt i gh tJUnCITOnplasmamemoraneso f a d j a c e n tc e l l si n t e r c eIlu l a rspacep a s s r v ge r u c o s ecarrer proternbasolateraIsurfacebasal amina-iEXTRACELLULARF L U I D / C O N N E C T-I V ETISSUEBLOODFigure 19-23 The role of tight junctionsin transcellulartransport.Transportproteinsare confinedto differentregionsof the plasmamembranein epithelialcellsThissegregationof the smallintestine.oermitsa vectorialtransferof nutrientsacrossthe epitheliumfrom the gut lumento the blood.In the examPleshown,glucoseis activelytransportedinto the cellby Na+-drivenglucosesymportsat itsapicalsurface,and it diffusesout of thecell by facilitateddiffusionmediatedbyglucosecarriersin its basolateralTightjunctionsarethoughttomembrane.confinethe transportproteinsto theirappropriatemembranedomainsby actingtheasdiffusionbarriersor"fences"withinlipid bilayerof the plasmamembrane;thesejunctionsalsoblockthe backflowofglucosefrom the basalsideoftheepitheliuminto the gut lumen.1152Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixFigure19-24Therole of tight junctionsin allowing epithelia to serveas barriersto solute diffusion.
(A)The drawing showshow a smallextracellulartracermoleculeaddedon one sideof an epitheliumispreventedfrom crossingthe epitheliumbythe tightjunctionsthat sealadjacentcellstogether.(B)Electronmicrographsof cellsinanepitheliumi n w h i c ha s m a l l ,extracellular,electron-densetracermoleculehasbeenaddedto eithertheapicalside(on the /eft)or the basolateralside(on the right).Inboth cases,the tightjunctionblockspassageof the tracer.(8,courtesyof DanielFriend.)(A)(B)fl 5*such as Na+,than the tight junctions in the epithelium lining the urinary bladder.These differencesreflect differencesin the proteins that form the junctions.Epithelial cells can also alter their tight junctions transiently to permit anincreased flow of solutes and water through breachesin the junctional barriers.Such paracellular transporf is especially important in the absorption of aminoacids and monosaccharides from the lumen of the intestine, where the concentration of these nutrients can increase enough after a meal to drive passivetransport in the proper direction.\t\4ren tight junctions are visualized by freeze-fracture electron microscopy,they seem to consist of a branching network of sealing strands that completelyencirclesthe apical end of each cell in the epithelial sheet (Figure r9-25A and B).In conventional electron micrographs, the outer leaflets of the two interactingmicrovilli(A)i n t e s t i n al u m e nr i d g e so f t r a n s m e m b r a n e l a t e r a lp l a s m ap a r t i c l e sf o r m i n g s e a l i n g m e m b r a n es t r a n d s( Pf a c e )u ) [m50 nmFigure19-25The structureof a tight junction betweenepithelialcellsof the smallintestine.Thejunctionsareshown(A)schematicalry,(B)in a freeze-fractureelectronmicrograph,and (C)in a conventionalelectronmicrograph.In (B),the planeof the micrographis parallelto theplaneof the membrane,and the tight junctionappearsasa bandof branchingsealingstrandsthat encircleeachcellin the epithelium.Thesealingstrandsareseenas ridgesof intramembraneparticleson the cytoplasmicfracturefaceof the membrane(thep face)or ascomplementarygrooveson the externalfaceof the membrane(theE face)(seeFigure19-26A).ln(C),the junctionis seenin crosssectionasaseriesof focalconnectionsbetweenthe outer leafletsof the two interactingplasmamembranes,eachconnectioncorrespondingto a sealingstrandin crosssection.(Band C,from N.B.Gilula,in CellCommunicationCox,ed.],pp.1-29.Newyork:Wiley,1974.)[R.P.11 5 3TIGHTJUNCTIONSANDTHEORGANIZATIONOFEPITHELIAi n t e r a c tni gp l a s m am e m b r a n e scell 1Ai ntercelIu lars p a c e(IIl o .6pmclaudinsealingstrandsoftightj unctionproteins \occludinproteinstight-junction(B)iccytoplasmhalf oflipid bilayercell1(A)plasma membranes are seen to be tightly apposed where sealing strands are present (Figure I9-25C).
Each tight junction sealing strand is composed of a longrow of transmembrane adhesion proteins embedded in each of the two interacting plasma membranes. The extracellular domains of these proteins adheredirectly to one another to occlude the intercellular space (Figure 19-26).The main transmembrane proteins forming these strands are the claud.ins,which are essentialfor tight junction formation and function. Mice that lack theclaudin-1gene, for example, fail to make tight junctions between the cells inthe epidermal layer of the skin; as a result, the baby mice lose water rapidly byevaporation through the skin and die within a day after birth. Conversely, ifnonepithelial cells such as fibroblasts are artificially caused to express claudingenes, they will form tight-junctional connections with one another.
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