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