Polarized cells, polarized views asymmetric cell division in hematopoietic cells

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REVIEWARTICLEpublished:03February2014doi:10.3389/fimmu.2014.00026

Polarizedcells,polarizedviews:asymmetriccelldivisionin

hematopoieticcells

KimPham1,2,FarukSacirbegovic3†andSarahM.Russell1,2,3,4*

1ImmuneSignallingLaboratory,PeterMacCallumCancerCentre,EastMelbourne,VIC,Australia2CentreforMicro-Photonics,FacultyofEngineeringandIndustrialSciences,SwinburneUniversityofTechnology,Hawthorn,VIC,Australia3DepartmentofPathology,UniversityofMelbourne,Melbourne,VIC,Australia4SirPeterMacCallumDepartmentofOncology,UniversityofMelbourne,Melbourne,VIC,Australia

Editedby:FrancescaDiRosa,ItalianNationalResearchCouncil,Italy

Reviewedby:SalvatoreValitutti,InstitutNationaldelaSantéetdelaRechercheMédicale,FranceDerkAmsen,SanquinBloodResearch,Netherlands

*Correspondence:SarahM.Russell,ImmuneSignallingLaboratory,PeterMacCallumCancerCentre,StAndrewsPlace,EastMelbourne,VIC3002,Australiae-mail:sarah.russell@petermac.org

†Presentaddress:FarukSacirbegovic,DepartmentofBiochemistryandMolecularBiology,MonashUniversity,Melbourne,VIC,AustraliaIthaslongbeenrecognizedthatalterationsincellshapeandpolarityplayimportantrolesin

coordinatinglymphocytefunctions.Inthelastdecade,anewaspectoflymphocytepolarity

hasattractedmuchattention,termedasymmetriccelldivision(ACD).ACDhaspreviously

beenshowntodictateorinfluencemanyaspectsofdevelopmentinmodelorganismssuch

asthewormandthefly,andtobedisruptedindisease.RecentobservationsthatACDalso

occursinlymphocytesledtoexcitingspeculationsthatACDmightinfluencelymphocyte

differentiationandfunction,andleukemia.DissectingtherolethatACDmightplayinthese

activitieshasnotbeenstraightforward,andtheevidencetodateforafunctionalrolein

lymphocytefatedeterminationhasbeencontroversial.Inthisreview,wediscusstheevi-

dencetodateforACDinlymphocytes,andhowitmightinfluencelymphocytefate.We

alsodiscusscurrentgapsinourknowledge,andsuggestapproachestodefinitivelytest

thephysiologicalroleofACDinlymphocytes.

Keywords:cellpolarity,asymmetriccelldivision,immunologicalsynapse,scribblecomplex,cellfate

INTRODUCTION

Aneffectiveimmuneresponsereliesonthecoordinationofsignals

tocontrolmajorcellfatecheckpointssuchasproliferation,differ-

entiation,survival,anddeath.Whilemanykeyplayers,including

surfacemolecules,transcriptionfactors,andcytokineshavebeen

identifiedtobeimportantforimmunecellfatecontrol,itisstill

notclearhowthesesignalsareintegratedduringthedifferentia-

tionandfunctionofBandTcells.Thesequestionsofhowsignals

areorchestratedduringcellfatedeterminationhavebeenpartic-

ularlywelladdressedinprogenitorcellsofthedevelopingworm

andfly.Inthesetwoorganisms,cellfateisstronglyinfluenced

bytheasymmetricdistributionoffatedeterminantsintothetwo

daughtersofadividingcell,knownasasymmetriccelldivision

(ACD)(1).ACDinvolvesthedifferentialpartitioningofprotein,

mRNA,microRNA,andothercellularconstituentsintothetwo

daughtercells.Therefore,ACDimpartsdifferentialfatessuchas

self-renewal,quiescence,proliferation,differentiation,andapop-

tosis.ThemechanismsandconsequencesofACDwereinitially

studiedinDrosophilamelanogasterneuronalprecursors,andC.

eleganszygoteformation,buthavenowbeenelucidatedinmany

tissues,includingthoseofmammals.Inthisreview,wedescribe

ourcurrentunderstandingofthemechanismsandconsequences

ofACDincellsofsolidtissues,discusstheevidencethatsim-

ilarprocessesmightapplyinhematopoieticprogenitorcells,B

cells,andTcells.Wealsodiscuss,whatwillberequiredtodeter-

minewhethertherearephysiologicalrolesforACDinlymphocyte

development,function,anddisease.THEROLEOFACDINSOLIDTISSUES

HomeostasisofstemcellsfrequentlyinvolvesACD,whereapar-

entcelldividestogenerateadaughtercellidenticaltoitself

(“self-renewal”),aswellasanotherdaughterthatisprogramed

toproliferate,differentiate,orboth(1).Insomeinstances,the

differentfatesofthetwodaughterscanoccurthroughstochas-

ticresponsesinwhicheachdaughterhassomeprobabilityof

eitherself-renewingoradoptingadifferentfatetomaintainan

appropriatebalanceofself-renewinganddifferentiatingprogeny

onapopulationlevel.Inotherinstances,thebalancebetweenself-

renewalanddifferentiationiscontrolledatthesinglecelllevel

byACD.AnexampleinwhichACDcontrolstheexpansionand

differentiationofthecellsoccursinthedevelopingDrosophila

centralnervoussystem(2)(Figure1A).Duringdevelopmentof

thelarvalcentralnervoussystem,neuroblastsdelaminatefrom

theneurepitheliumtoundergoupto20roundsofACD,each

roundcreatinganotherneuroblast(“self-renewal”)andaganglion

mothercell(GMC)thatcanfurtherproliferateanddifferentiate

toformmatureneurons.Neuroblastsbecomequiescentduring

pupationbutthenre-enterthecellcycleandreinitiateACDfor

furtherroundsofproliferationanddifferentiation(1).Thelimited

setofneuroblaststhereforeundergoescontrolledACDthatcon-

tributestothethousandsofadultneuronsandneuronalassociated