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5n mprasmamemoraneo f c e l l2h i n g er e g i o n< 0.05 mM Ca2+c a d h e r i nr e p e a t(A)domainFigure19-9 Cadherinstructureand function.(A)Theextracellularhow two suchis shownhere,illustratingof a classicalcadherin(C-cadherin)end-tomoleculeson oppositecellsarethoughtto bind homophilically,end.The structurewas determinedby x-raydiffractionof the crystallizedpart of eachC-cadherinextracellulardomain.(B)Theextracellularpolypeptideconsistsof a seriesof compactdomainscalledcadherinjoined by flexiblehingeregions.Ca2+bindsin the neighborhoodrepeats,of eachhinge,preventingit from flexing.In the absenceof Ca2+,themoleculebecomesfloppyand adhesionfails.(C)At a typicaljunction,functioninglikeVelcrotomanycadherinmoleculesarearrayedin parallel,hold cellstogether.Cadherinson the samecellarethoughtto be coupledby side-to-sideinteractionsbetweentheir N-terminalheadregions,and viathe attachmentsof their intracellulartailsto a mat of other proteins(notshown here).(Basedon T.J.Boggonet al.,Science296:1308-1313,2002.With permissionfrom AAAS.)types of transmembrane adhesion proteins.
The making and breaking ofanchoring junctions plays a vital part in development and in the constantturnover of tissues in many parts of the mature body. <CGAA>(c)VertebrateCellsSelectiveCell-CellAdhesionEnablesDissociatedinto OrganizedTissuesto ReassembleCadherins form specific homophilic attachments, and this explains why thereare so many different family members. Cadherins are not like glue, making cellsurfaces generally sticky.
Rather, they mediate highly selective recognition,enabling cells of a similar ty?e to stick together and to stay segregatedfromother types of cells.This selectivity in the way that animal cells consort with one another wasdemonstrated more than 50 years ago, Iong before the discovery of cadherins, inexperiments in which amphibian embryos were dissociated into single cells.These cells were then mixed up and allowed to reassociate.
Remarkably, the dissociated cells often reassembled in uitro into structures resembling those of theoriginal embryo (Figure f9-10). The same phenomenon occurs when dissociated cells from two embryonic vertebrate organs, such as the liver and the retina,are mixed together and artificially formed into a pellet: the mixed aggregatesFigure19-10 Sortingout. Cellsfromdifferentpartsof an earlyamphibianembryowill sortout accordingto theirexperimentshownorigins.In the classicalhere,mesodermcells(green),neuralplatecells(b/ue),and epidermalcells(red)haveand thenbeendisaggregatedin a randommixture.Theyreaggregatedreminiscentsortout into an arrangementof a normalembryo,with a "neuraltube"internally,epidermisexternally,andmesodermin between.(ModifiedfromP.L.Townesand J.
Holtfreter,J. Exp.Zool.128'53-120,1955.With permissionfromWiley-Liss.)1140Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixFigure19-11 Selectivedispersaland reassemblyof cellsto form tissuesin a vertebrateembryo.Somecellsthat areinitiallypart of the epithelialneuraltube altertheiradhesivepropertiesand disengagefrom theepitheliumto form the neuralcreston the uppersurfaceofthe neuraltube.Thecellsthen migrateawayand form a varietyof celltypesandtissuesthroughoutthe embryo.Herethey areshownassemblinganddifferentiatingto form two clustersof nervecells,calledganglia,in theperipheralnervoussystem.Whilesomeof the neuralcrestcellsdifferentiatein the ganglionto becomethe neurons,othersbecomec e l l st h a t w i l l::ffi:tti"l;;,;[iL1d,#h',,:'#]ii#'.*']:*l'ii:flgradually sort out according to their organ of origin.
More generally, disaggregated cells are found to adhere more readily to aggregatesof their own organthan to aggregatesofother organs. Evidently there are cell-cell recognition systems that make cells of the same differentiated tissue preferentiallv adhere toone anotherSuch findings suggestthat tissue architecture in animals is not just a product of history but is actively organized and maintained by the system of affinitiesthat cells have for one another and for the extracellular matrix. In the developing embryo, we can indeed watch the cells as they differentiate, and see howthey move and regroup to form new structures, guided by selective adhesion.Some of these movements are subtle, others more far-reaching, involving longrange migrations, as we shall describe in chapter 22.rnvertebrate embryos, forexample, cells from rhe neural crestbreakaway from the epithelial neural tube,of which they are initially a part, and migrate along specific paths to many otherregions.
There they reaggregatewith other cells and with one another to form avariety of tissues, including those of the peripheral nervous system (Figurer9-l t). To find their way, the cells depend on guidance from the embryonic tissues along the path. This may involve chemotaxis or chemorepulsion, that is,movement under the influence of soluble chemicals that attract or repel migrating cells. It may also involve contact guidance,inwhich the migrant cell touchesother cells or extracellular matrix components, making transient adhesions thatgovern the track taken.
Then, once the migrating cell has reached its destination,it must recognize and join other cells of the appropriate type to assembleinto atissue. In all these processesof sorting out, contact guidance, and tissue assembly, cadherins play a crucial part.IIr,o*o'o,oEe,ooq;6Iooo^roo'on,p e r i p h e r agl a n g l i aCadherinsControlthe 5electiveAssortmentof CellsThe appearance and disappearanceof specific cadherins correlate with steps inembryonic development where cells regroup and change their contacts to create new tissue structures. As the neural tube forms and pinches off from theoverlying ectoderm, for example, neural tube cells lose E-cadherin and acquireother cadherins, including N-cadherin, while the cells in the overlying ectodermcontinue to expressE-cadherin (Figure ls-lzL, B).
Then, when the neural crestcells migrate away from the neural tube, these cadherins become scarcelydetectable, and another cadherin (cadherin-7) appears that helps hold thestudies with cultured cells support the suggestionthat the homophilic binding of cadherins controls these processesof tissue segregation.In a line of cultured fibroblasts called L cells,for example, cadherins are not expressedand thecells do not adhere to one another. \Mhen these cells are transfected with DNAencoding E-cadherin, however, they become adherent to one another, and theadhesion is inhibited by anti-E-cadherin antibodies.
Since the transfected cellsdo not stick to untransfected L cells, we can conclude that the attachment1141CADHERINSAND CELL-CELLADHESIONdepends on E-cadherin on one cell binding to E-cadherin on another. If L cellsexpressing different cadherins are mixed together, they sort out and aggregateseparately,indicating that different cadherins preferentially bind to their owntype (Figure l9-l3A), mimicking what happens when cells derived from tissuesthat expressdifferent cadherins are mixed together.A similar segregationof cellsoccurs if L cells expressing different amounts of the same cadherin are mixedtogether (Figure l9-l3B).
It therefore seems likely that both qualitative andquantitative differences in the expressionof cadherins have a role in organizingtissues.TwistRegulatesEpithelial-MesenchymalTransitionsThe assembly of cells into an epithelium is a reversible process.By switching onexpression of adhesion molecules, dispersed unattached cells-often calledmesenchymal cells-can come together to form an epithelium. Conversely,epithelial cells can change their character, disassemble, and migrate away fromtheir parent epithelium as separate individuals.
Such epithelial-mesenchymaltransitionsplay an important part in normal embryonic development; the originof the neural crest is one example (seeFigure 19-11).A control system involvinga set of gene regulatory components called Slug, Snail, and TWist,with E-cadherin as a downstream component, seems to be critical for such transitions: inseveraltissues,both in flies and vertebrates,switching on expressionof TWist,forexample, converts epithelial cells to a mesenchymal character, and switching itoff does the opposite.Epithelial-mesenchymal transitions also occur as pathological events during adult life, in cancer.Most cancers originate in epithelia, but become dangerously prone to spread-that is, malignant-only when the cancer cells escapefrom the epithelium of origin and invade other tissues.Experiments with malignant breast cancer cells in culture show that blocking expression of TWist canconvert them back toward a nonmalignant character.
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