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Theactincortex:abridgebetweencellshapeandfunctionKevinJ.Chalut1,EwaK.Paluch2,31WellcomeTrust/MedicalResearchCouncilStemCellInstitute,UniversityofCambridge,UnitedKingdom;2MRC-LMCB,UniversityCollegeLondon,London,UnitedKingdom;3InstituteforthePhysicsofLivingSystems,UniversityCollegeLondon,London,UnitedKingdom.Correspondence:[email protected]@ucl.ac.ukPrecisecontrolofcellmorphogenesisisakeytohealthycellphysiology,andcellshape
deregulationisattheheartofmanypathologicaldisorders.Changesincellshapestrongly
correlatewith,ifnotcause,processessuchascellmigration,tissuehomeostasis,epithelial-
amoeboid-mesenchymaltransitionsandcellulardifferentiation(Figure1).Infact,early
embryologistsdefinedmanycellfatechangesbasedoncellmorphology,andusedcell
shapeasaprimaryidentifierofdifferentnascenttissues.Here,wediscussthecontrolofcell
shapeandmechanics,andtheemergingrelationshipbetweenshape,biochemicalsignaling
andcellularfunction,highlightingremaininggapsinourunderstandingandpotential
directionsoffutureinvestigations.
Cellshapeisdefinedbycellularmechanicalpropertiesandbythecell’sphysicalinteractions
withitsenvironment.Mostcelldeformationsaredrivenbychangesinthephysical
propertiesofthecellsurface,whicharedominatedbythemechanicsofthecellularcortex.
Thecortexisathinnetworkofactinthatliesunderandistetheredtotheplasma
membraneinmostanimalcells.Corticalactinfilamentsareorganizedinameshworkcross-
linkedbyspecificproteinsandbymyosinmotors,whichgeneratecontractilestressesinthe
network(Clarketal.,2014).Thesestressesgiverisetocorticaltension,whichdetermines
globalcellsurfacemechanics.Gradientsincorticaltensionresultincorticalflowsand
cellularcontractions,suchasthosedrivingcleavagefurrowingression,cellbodyretraction
duringcellmigrationandepithelialcontractionsunderlyingtissueconstrictionevents
(LevayerandLecuit,2012).
Overthepastdecade,anincreasingnumberofbiologicalandbiophysicalinvestigations
havefocusedontheactincortex.Cortexcompositionhasbeencharacterizedbymass
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spectrometryusingisolatedcellularblebstocollectsufficientamountsofcorticalmaterial
(Bovellanetal.,2014).Corticalactinnucleatorsandvariousregulatorsofcortical
contractilityhavebeenidentified(Bovellanetal.,2014;Luoetal.,2013),andtoolsare
availabletomeasurephysicalcharacteristics,suchascorticaltensionandthickness
(reviewedin(Clarketal.,2014)).Themechanicsofcorticalcontractionsandflowsinmany
morphogeneticeventshavebeendissected,includingC.eleganszygotepolarization(Mayer
etal.,2010),mouseembryocompaction(Maitreetal.,2015)andepithelialconstrictionsin
theDrosophilaembryo(LevayerandLecuit,2012).However,mostpaststudieshave
focusedonthecortexinitself.Incontrast,muchlessisknownabouthowthecortexis
dynamicallyregulatedbyspecificsignalingpathways,howitinturntriggersbiochemical
signalingevents,andhowcorticalprocessesareintegratedwithinthecelltodrive
morphogenesis.
Manymorphogeneticprocessesappeartobedrivenbytransitionsbetweenacorticalanda
stressfiberdominatedorganizationofintracellularactinnetworks.Stressfibersarequasi
one-dimensionalbundlesofactinfilamentsusuallyconnectingtwoadhesionpoints,
whereasinthecortex,actinformsaroughlyisotropicmeshworkundertheplasma
membrane(Figure2).Whilethemolecularregulationofboththecortexandstressfibers
arereasonablywellunderstood,howtransitionsbetweenthesetwotypesofnetworksare
controlledremainselusive.Forexample,duringdevelopmentaltransitionssuchasexitfrom
naïvepluripotencyorduringepithelialtomesenchymaltransitions(EMT),actinreorganizes
fromamostlycorticalarrangementintostressfibersandlamellipodia(Figure1).Howthis
reorganization,whichdrivescellspreading,isregulatedbythesignalingpathwaysdriving
cellstatechangessuchascelldifferentiationisnotunderstood.
Transitionsinactinnetworkorganizationarealsoassociatedwithchangesinthewaythe
cellinteractswiththeenvironment.Stressfibersareusuallyconnectedtoandpromotethe
formationofintegrin-basedfocaladhesions(LivneandGeiger,2016),whereascorticalactin
isoftenassociatedwithcadherin-basedcell-celladhesions(Engletal.,2014).Interestingly,
cell-cellcontactformationisconcomitantwithcorticalclearinginthecontactzone(Maitre
etal.,2012)whileactindynamicsandtensioninturninfluencecadherinrecruitment(Engl
etal.,2014).Thus,thecell’sinteractionswithneighborsandmatrixarecontrolledviaa
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subtlecross-talkbetweenactinorganization,contractility,dynamicsandcontactswith
integrinsand/orcadherins.Onefuturechallengewillbetofullyunderstandthiscross-talk,
andhowitismodulatedduringcellularshapechangesassociatedwithdevelopmentalfate
transitions.Extendingthealreadybroadlibrariesofactinbindingproteinsandidentifying
connectionstoadhesionsmayprovideonepathtowardsthisgoal.Theseextensionscanin
turninstructgain-andloss-of-functionstudiestoshedlightonthechangestocellshapeand
fatethataccompanydevelopmentalprocesses.
Anotherkeyyetpoorlyunderstoodaspectoftheactincytoskeletonfunctionin
developmentisitsroleincellularsignaling.Indeed,actinnetworksnotonlycontrolcell
shape,theyalsoareacenterofbothmechanicalandbiochemicalsignaling.Forexample,
focaladhesionmaturationisdrivenbytensioninstressfibers,whichupregulatesfocal
adhesionkinaseandSrcfamilykinasebasedsignaling.Thesekinasesareupstream
mediatorsofmitogenactivatedproteinkinase(MAPK)signaling,whichisessentialfora
multitudeofcellularprocessesincludingdifferentiation.Moreover,thereisfeedbackfrom
MAPKsignalingtotheactincytoskeleton:actinorganizationandcontractilityisregulatedby
interactionsbetweenErkandRhoGTPases(Vialetal.,2003).Thoughlessstudied,similar
interactionsarepossiblebetweencadherin-basedadhesionsandWntsignaling,both
canonicalandnon-canonical(HeubergerandBirchmeier,2010).Itislikelythatthe
connectionbetweenactinnetworksandcellularadhesionsdrivesmanyotherbiochemical
signalingfeedbackloops,raisingthetantalizingpossibilitythatactinorganizationandcell
shapearemorethanpassivedownstreamplayersincellulartransformationssuchas
differentiation.
Thepossibilitythatactinactivelyregulatescellfunctionisbuttressedbythefactthatthere
areatleasttwootherconnectionsbetweenactinorganizationandsignaling.First,actin
dynamicsitselfcaninfluencegeneexpression.Changesinactinorganizationarelikelyto
modifytheintracellularfilamentous(F)tomonomeric(G)actinratiobothinthecytoplasm
and,becauseactinisactivelyshuttledintoandoutofthenucleus,inthenucleus.Increasing
levelsofG-actininthenucleusaffectstranscription,bothduetointeractionswithallthree
typesofRNApolymeraseandalsobecauseitisinvolvedinthenuclearexportofmyocardin-
relatedtranscriptionfactors(MRTFs).Forexample,iflessG-actinisavailableinthenucleus
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(perhapsbecauseofincreasedlevelsofpolymerizedactininthecell)thenMRTFfamily
membersinturnactivatetheserumresponsefactor(SRF)pathway.SRFactivates
immediateearlygenessuchasc-fos(PosernandTreisman,2006),whichplaymajorrolesin
cellulartransformationssuchasdifferentiationandoncogenesis.Second,thecortexis
physicallyconnectedtothenucleusviacytoplasmicstructuralcomponents,andstressesat
thecellsurfacecantranslatetostrainonthenucleus(Pagliaraetal.,2014).Increasedstress
intheactincytoskeletoncanactthroughtheLINCcomplexonthenuclearmembraneand
thenuclearlaminstofurthertunebiochemicalsignaling.Forexample,increased
cytoskeletalstresscanstabilizelaminA/CwhichactivatesSRFandtheretinoicacid
pathways,andfurthermoreactsasamediatorofMAPKsignaling(Swiftetal.,2013)and
activationofimmediateearlygenes.Thereisalsonewevidencethatstressthroughthe
actincytoskeletoncanactdirectlythroughemerins(alsonuclearmembraneproteins)to
facilitatepolycomb-mediatedgenesilencingatthenuclearenvelope(Leetal.,2016).
Itistemptingtogiveintodespairwhenconsideringthemyriadofwaysinwhichtheactin
cytoskeletonaffectssignalingandviceversa.However,itappearsthatthenexusofactin-
regulatedsignalingandshapemaybeactinnetworkorganization.Thus,tofullyunderstand
therelationshipbetweencellshapeandcellfunction,wemustfirstunderstandthe
transitionsbetweendifferenttypesofactinnetworks.Then,cytoskeletalinvestigations
mustbefullyintegratedwithstudiesofsignalingpathwaysthatdrivecellstatechanges.
Truecomprehensionoftheinterplaybetweenactinnetworktransitionsandcellstate
transitionswillrequireaninterdisciplinarypushinvolvingbiophysicists,molecularandcell
biologistsstudyingthecytoskeleton,developmentalbiologistsandstemcellbiologists.
Acknowledgements:
KJCacknowledgessupportfromtheRoyalSociety,MedicalResearchCouncilUKand
WellcomeTrust(forcorefundingtotheCambridgeStemCellInstitute).EKPacknowledges
supportfromtheMedicalResearchCouncilUK(corefundingtotheLMCB).WethankCéline
LabouesseandMurielleSerresforprovidingtheimagesforthefigures.
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Figure1:Embryonicstemcellsinanaïvephaseofpluripotency(A)andafterexitfromnaïve
pluripotency(B).Duringthistime,actin(incyan)transitionsfromcorticalactintostress
fibersasthecellsspread.Nucleiarelabeledinred.
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Figure2:Differenttypesofactinnetworksininterphase(A)andmitotic(B)HeLacells
stainedwithDAPItodetectDNA(red)andphalloidintomarkF-actin(cyan).Interphasecells
arespreadandactinisprimarilyorganizedinstressfibers.Mitoticcellsareroundedand
actinispredominantlycortical.
A B
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