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It does not, however, stop macrophages, l1'rnphocytes, or nerve processesfrom passing through it, using specializedproteaseenzyrnesto cut a hole for their transit. The basal lamina is also important in tissue regeneration after injury. When cells in tissues such as muscles, nerves, andepithelia are damaged or killed, the basal lamina often survives and provides ascaffold along which regenerating cells can migrate. In this way, the original tissue architecture is readily reconstructed.A particularly striking example of the role of the basal lamina in regeneration comes from studies on the neuromuscular junction, the site where thenerve terminals of a motor neuron form a chemical synapsewith a skeletalmuscle cell (discussedin Chapter I l). In vertebrates,the basal lamina that surroundsthe muscle cell separatesthe nerve and muscle cell plasma membranes at theslmapse,and the synaptic region of the lamina has a distinctive chemical character, with special isoforms of type IV collagen and laminin and a proteoglycancalled agrin.This basal lamina at the synapse has a central role in reconstructing thesynapse after nerve or muscle injury.
If a frog muscle and its motor nerve aredestroyed,the basal lamina around each muscle cell remains intact and the sitesof the old neuromuscular junctions are still recognizable.If the motor nerve, butnot the muscle, is allowed to regenerate,the nerve axons seek out the originalsynaptic sites on the empty basal lamina and differentiate there to form normallooking nerve terminals. Thus, the junctional basal lamina by itself can guide theregeneration of motor nerve terminals.Similar experiments show that the basal lamina also controls the localization of the acetylcholine receptors that cluster in the muscle cell plasma membrane at a neuromuscular junction.
If the muscle and nerve are both destroyed,but now the muscle is allowed to regeneratewhile the nerve is prevented fromdoing so, the acetylcholine receptors synthesized by the regenerated muscleIocalize predominantly in the region of the old junctions, even though the nerveis absent (Figure f 9-44). Thus, the junctional basal lamina apparently coordinates the local spatial organization of the components in each of the two cellsthat form a neuromuscular junction.
Some of the molecules responsible forthese effects have been identified. Motor neuron €xons, for example, depositagrin in the junctional basal lamina, where it regulates the assembly of acetyl-s h e l lo fr e s i du abasal am u s c l ec e l lc u t s ot h a t i tdegeneratesREGENERATEDNERVEFIBERttr junctionali'basallamina:(\,DEGENERATEMDUSCLEAND NERVEREGENERATEDMUSCLEFIBERFigure 19-44 Regenerationexperimentsdemonstratingthe specialcharacterofthe junctionalbasallaminaat arratednervejunction.Whenthe nerve,neuromuscularrcturrrstositeo{but not the muscle,is allowedtooriginal junctionregenerateafter both the nerveandmusclehavebeendamaged(upperpart offigure),the junctionalbasallaminadirectsnerveto the originalthe regeneratingsynapticsite.Whenthe muscle,but notthe nerve,is allowedto regenerate(/owerpart of figure),the junctional basallaminan e w a c e t y l c h o l i n e causesnewlymadeacetylcholinereceptorsbecomereceptors(blue)to accumulateat theconcentratedatoriginalsynapticsite.The muscles i t eo f o r i g i n a lregeneratesfrom satellitecells(discussedjunctionin Chapter23)locatedbetweenthe basallaminaand the originalmusclecell(notshown).Theseexperimentsshowthat thejunctionalbasallaminacontrolsthelocalizationof synapticcomponentsonboth sidesof the lamina.INTEGRINSAND CELL*MATRIXADHESIONcholine receptors and other proteins in the junctional plasma membrane of themuscle cell.
Reciprocally,muscle cells deposit a particular isoform of laminin inthe junctional basal lamina, and some evidence suggeststhat this binds directlyto the extracellular domain of voltage-gated Caz* channels in the presynapticmembrane of the nerve cell, helping to hold them at the synapsewhere they areneeded. Both agrin and the synaptic isoform of laminin are essentialfor the formation of normal neuromuscular junctions.
Defects in components of the basallamina or in proteins that tether muscle cell components to it at the synapseareresponsible for many of the forms of muscular dystrophy, in which muscles atfirst develop normally but then degeneratein later years of life.SummaryThe basal lamina is a thin tough sheetof extracellular matrix that closely underliesepithelia in all multicellular animals. It also wraps around certain other cell rypes,such as muscle cells.AII basal laminae are organized on a framework of lamininmolecules,linked togetherby their side-armsand held closebeneath the basal endsofthe epithelial cellsby attachment to integrins and other receptorsin the basal plasmamembrane.
TypeN collagen moleculesare recruited into this structure, assemblinginto a sheetlikemesh that is an essentialcomponent of all mature basal laminae. Thecollagen and laminin networks in mature basal laminae are bridged by the proteinnidogen and the large heparan suffate proteoglycanperlecan.Basal laminae prouide mechanicel support for epithelia; theyform the interfaceand the attachment betweenepithelia and connectiuetissue;they serueasfilters in thekidney; they act as barriers to keepcells in their proper compartments; they influencecell polarity and cell dffirentiation; theyguide cell migrations;and moleculesembedded in them help to organize elaborate structures such as neuromuscular synapses.When cellsare damaged or killed, basal laminae often suruiueand can help guide tissue regeneration.INTEGRINSANDCELL_M RIXADHESIONCells make extracellular matrix, organize it, and degrade it. The matrix in its turnexerts powerful influences on the cells. The influences are exerted chieflythrough transmembrane cell adhesion proteins that act as matrix receptors.These tie the matrix outside the cell to the cltoskeleton inside it, but their rolegoesfar beyond simple passivemechanical attachment.
Through them, components of the matrix can affect almost any aspect of a cell's behavior. The matrixreceptors have a crucial role in epithelial cells, mediating their interactions withthe basal lamina beneath them; and they are no less important in connectivetissue cells, for their interactions with the matrix that surrounds them.Severaltypes of molecules can function as matrix receptors or co-receptors,including the transmembrane proteoglycans.But the principal receptors on animal cells for binding most extracellular matrix proteins are the integrins.
Likethe cadherins and the key components of the basal lamina, integrins are part ofthe fundamental architectural toolkit that is characteristic of multicellular animals. The members of this large family of homologous transmembrane adhesion molecules have a remarkable ability to transmit signals in both directionsacrossthe cell membrane. The binding of a matrix component to an integrin cansend a messageinto the interior of the cell, and conditions in the cell interiorcan send a signal outward to control binding of the integrin to matrix (or, insome cases,to a cell-surface molecule on another cell, as we saw in the case ofwhite blood cells binding to endothelial cells).
Tension applied to an integrincan cause it to tighten its grip on intracellular and extracellular structures, andloss of tension can loosen its hold, so that molecular signaling complexes fallapart on either side of the membrane.
In this way, integrins can also serve notonly to transmit mechanical and molecular signals,but also to convert the onetype of signal into the other. Studies of the structure of integrin molecules havebegun to reveal how they perform these tasks.1169'1170 Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixe x t r a c e l l u l amr a t r i xo r o t e i nlntegrinsAreTransmembraneHeterodimersThatLinkto theCytoskeletonThere are many varieties of integrins-at Ieast 24 in humans-but they all conform to a common plan. An integrin molecule is composed of two noncovalentlyassociated glycoprotein subunits called u, and B. Both subunits span the cellmembrane, with short intracellular C-terminal tails and large N-terminal extracellular domains.
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