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Thecomplexityofthecentralnervoussystem(CNS),withhundredsofdistinctneuronalcelltypes,emphasizestheimportanceofunderstandingtheprinciplesofhowdifferenttypesofneuronsdevelop.
Duringdevelopment,positionalinformationisprovidedbyextrinsicsignalingfactors.
Signalingleadstothepatternedexpressionoftranscriptionfactorswithindistinctdomainsofproliferatingprogenitorcells[1].
Thefateofpost-mitoticneurons–neuronsthathaveexitedthecellcycleandstartedtodifferentiate–isdeterminedbycombinationsoftranscriptionfactorsexpressedintheprogenitorcells.
Post-mitoticdifferentiatingneuronsmigrate,oftentoremotedestinations,andbecomeorganizedintodistinctbrainnucleiorcelllayers.
Neuronalfateisfurtherspecifiedandmaintainedbycomplexesoftranscriptionfactorsexpressedinthepost-mitoticmaturingneurons[2].
MidbraindopamineneurondevelopmentDopamine-secretingneurons(DAneurons)developingwithintheventralmidbrainareclinicallyimportantcells.
Notably,themajormotorsymptomsinpatientswithParkinson'sdiseasearecausedbyDAneurondegeneration.
Severalotherdisorders,includingschizophreniaandaddiction,areassociatedwithabnormaldopamineneurotransmission.
Thus,theprospectofengineeringDAneuronsfromstemcellshasattractedconsiderableinterestasitcouldprovideopportunitiesformoreadvancedinvitrocellularmodels,allowingrefinedmethodsfordrugdevelopment,andforcellreplacementinpatientswithParkinson'sdisease.
However,stem-cellengineeringrequiresdetailedknowledgeofhowDAneuronsaregeneratedinnormalembryogenesis,whichinpartexplainsastrongfocusinpreviousstudiesonventralmidbraindevelopment[3].
AlthoughkeysignalingeventsandtranscriptionfactorsimportantforthedevelopmentofallDAneuronshavebeenidentified,muchremainstobeuncovered.
Notably,themidbrainDAneuronscanbesubdividedintoseveralanatomicallyandfunctionallydistinctsubgroups,butlittleisknownabouthowthesedifferenttypesarespecified.
Therostrally,laterallylocatedDAneuronsofthesubstantianigraparscompacta(SNc)areinvolvedinmotorcontrol,andarethecellsthatmainlyundergodegenerationinParkinson'sdisease.
Neuronsoftheventraltegmentalarea(VTA)andretrorubalfieldarelocatedatacaudal,medialpositionintheventralmidbrainandarepartofthemesocorticolimbicsystem.
Abnormalfunctioningofthelimbicsystemisassociatedwithpsychiatricdisorders,includingaddictionandschizophrenia.
ThedifferenttypesofDAneuronsresembleeachotherbuttheiraxontargetsaredistinct.
NeuronsoftheSNcinnervatethedorsalstriatumwhileVTAneuronsmainlyinnervatethemoreventrallylocatednucleusaccumbensandtheprefrontalcortex.
ItremainsunclearifthesedistinctDAneuronsubtypesaredevelopmentallyspecifiedatanearlyprogenitorstageorifeventsinpostmitoticneuronsdeterminetheirsubtypeidentity.
Moreover,althoughrecentstudieshavedefinedmolecularmarkersthatareuniquelyexpressedindistinctDAneuronprogenitordomains,thelineagerelationshipsbetweenspatiallydistinctprogenitorsanddifferentDAAbstractManypreviousstudieshavefocusedonunderstandinghowmidbraindopamineneurons,whichareimplicatedinmanyneurologicalconditions,aregeneratedduringembryogenesis.
Oneoftheremainingquestionsconcernshowdifferentdopamineneuronsubtypesarespecified.
ArecentpaperinNeuralDevelopmenthasrevealedfeaturesofaspatialandtemporallineagemapthat,togetherwithotherstudies,beginstoelucidatethedevelopmentaloriginofdistinctneuronalsubtypeswithinthedevelopingmidbrain.
TracinglineagestouncoverneuronalidentityLiaPanman1andThomasPerlmann1,2*Seeresearcharticlehttp://www.
neuraldevelopment.
com/content/6/1/29COMMENTARYOpenAccess*Correspondence:thomas.
perlmann@licr.
ki.
se1LudwigInstituteforCancerResearchLtd,Box240,17177Stockholm,SwedenFulllistofauthorinformationisavailableattheendofthearticle2011PanmanandPerlmann;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
PanmanandPerlmannBMCBiology2011,9:51http://www.
biomedcentral.
com/1741-7007/9/51neuronsubtypesremainunclear.
ArecentstudypublishedinNeuralDevelopmentbyBlaessetal.
[4]providesnewinsightsintotheseimportantquestions.
LineageanalysisofventralmidbrainDAneuronsAfterexitingthecellcycle,post-mitoticneuronsmigratetodistinctpositionswithintheCNS.
Itisthereforedifficulttopredictthespatialandtemporaloriginofspecificneuronalsubtypessolelyfromanalysisofgeneexpressioninprogenitorcellsorfromanalysisofdifferentmousemutants.
Blaessetal.
[4]overcamethisproblembyusingatechniquecalledgeneticinduciblefatemapping(GIFM)toassesslineagerelationshipswithinthedevelopingventralmidbrain.
GIFMdependsonusingmiceengineeredtoexpressaninducibleCrerecombinaseinspecificprogenitorcells.
Aftercrossingsuchmicewithmicethatexpressreportergenes–forexample,enhancedyellowfluorescentprotein–onlyafterCre-mediatedrecombination,specificallytimedinductionoftherecombinaseresultsinpermanentmarkingofspecificprogenitorcellsandtheirdescendants.
GIFMhasbeenusedsuccessfullyinmanystudies–forexample,todeterminethelineageofserotonergicprogenitorcells[5],whichledtonewinsightsinrhombomere-specificcontributionstodistinctserotonergicnuclei.
Inaddition,thetimingoftheestablishmentofalineage-restrictionboundarybetweenthemesencephalon(theembryonicmidbrain)andrhombomere1ofthehindbrainhasbeendeterminedusingGIFM[6].
TostudytheoriginsofmidbrainDAneurons,Blaessetal.
usedmousestrainsinwhichCreactivitycouldbetemporallycontrolledbytamoxifenadministration,whichswitchesontheCrerecombinase,tomarkventralmidbrainprogenitorcellsexpressingsonichedgehog(Shh)andtheShhtargetgeneGli1.
Innormaldevelopment,expressionofbothgenesisinitiatedinprogenitorcellsatthemidbrainventralmidlineandsubsequentlyextendslaterally,withGli1expressionprecedingthatofShh.
ApreviousstudybyJoksimovicetal.
[7]usedanidenticalapproachtomarkShh-expressingcells.
ThesestudiesexploitedthedynamicexpressionpatternsofShh[4,7]andGli1[4]combinedwithtemporallycontrolledGIFMtofollowthefateofdistinctventralmidbrainprogenitorpools.
BothBlaessetal.
[4]andJoksimovicetal.
[7]showedthatdistinctprogenitorpoolscouldbelabeledusingGIFM.
Earlytamoxifentreatmentlabeledamedialcellgroup(thatis,cellsnearesttothemidline)whereasadministrationoftamoxifenatlatertimepointslabeledprogressivelymorelateralprogenitors.
TheseresultsshowedthatthelateralexpansionofShhandGli1expressionisduetoinducedexpressionindistinctprogenitorsratherthanthelateralgrowthofearlyShh-expressingprogenitors.
Lineagemapswerederivedbyanalyzingthefateatembryonicday18[7]orpostnataldays21to30[4]ofShh-andGli1-expressingprogenitorsthathadbeenmarkedatdifferenttimes.
Joksimovicetal.
[7]concludedthattheearlyShh-expressingmedialprogenitorsmainlygiverisetoneuronsoftheVTA,whereasBlaessetal.
[4]foundthatthesecellswerepreferentiallygeneratingneuronsoftheSNc.
Unexpectedly,Blaessetal.
alsoconcludedthatlabeledlateralprogenitorcellsgaverisetoastrocytes,whereasmedialprogenitorcellsdidnotshowanygliogenicpotential[4].
BothstudiesconsistentlydefinedapopulationofmorelateralandlateShh-expressingprogenitorsthatpreferentiallygiverisetoneuronsoftheVTAbutnottheSNc.
Thediscrepanciesbetweenthetwostudiescanprobablybeexplainedbydifferencesinthewaysthatthelineagemapswerederived.
Forexample,thetwostudiesanalyzeddifferentmarkersandthefate-mappedcellswereanalyzedatdifferenttime-points.
Regardlessofthesedifferences,however,bothstudiesconclusivelyshowthatdistinctShh-expressingprogenitorpoolsgiverisetodistincttypesofDAneuronsasdefinedatlaterembryonicorpostnatalstages.
Althoughthesestudiesprovideusefulresultsthatbegintoelucidatealineagemapofseveraldifferentcelltypesoftheventralmidbrain,theydonotrevealthemechanismsbywhichdistinctDAneuronsubtypesarespecified.
WhilefindingsthatdistinctprogenitorpoolsgiverisetodifferenttypesofDAneuronssuggestthatmoleculardifferencesinprogenitorsmightdeterminetheidentityofthedifferentsubtypes,itisalsopossiblethatspecificationeventstakeplaceatpostmitoticstages.
Indeed,thetranscriptionfactorPitx3,whichisexpressedinpostmitoticDAneurons,isimportantforthenormaldevelopmentofSNcbutnotVTAneurons[8].
PostmitoticexpressionofOtx2wasrecentlyshowntoberequiredforcontrollingtheidentityofGirk2-negativeVTAneuronsexpressinglowlevelsoftheglycosylateddopaminetransporter[9].
TheneurotoxinMPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl)selectivelydestroysdopaminergicneuronsoftheSNcandinducesparkinsoniansymptoms,whileVTAneuronsarerelativelyspared.
OneofthedifferentiatedcharacteristicsofVTAneuronsconferredbyOtx2ishigherresistancetoMPTP.
OtherstudieshavealsobeguntodefinemoleculardifferencesbetweenmedialandlateralDAneuronprogenitorcellsthatmayrelatetoDAneuronsubtypespecification.
AremarkablefeatureofthedevelopmentofDAneuronsisthattheycanbegeneratedatthemidbrainventralmidlinefromfloorplatecellswithglia-likecharacteristics.
Incontrast,floorplatecellswithintheventralmidlineofthehindbrainandspinalcordareunabletogiverisetoneurons.
Thus,themidbrainPanmanandPerlmannBMCBiology2011,9:51http://www.
biomedcentral.
com/1741-7007/9/51Page2of3floorplatecellsareuniqueintheirneurogeniccapacity.
TheDAneuronprogenitorzonecanbemolecularlydefinedasfloorplatecellsexpressingthecellsurfaceproteinCorinandShh,thelatteronlyexpressedathighlevelsatearlystagesofdevelopment,togetherwithmorelateralneuronalprogenitorsthatlackfloorplatecharacteristicsandselectivelyexpressthesignalingproteinWnt1(Figure1).
BothShhandWnt1arecriticalsignalingmoleculeswithimportantfunctionsformanytypesofdevelopingneurons,includingDAneurons.
Interestingly,downregulationofShhexpressionwithintheventralmidlinehasbeenshowntobeessentialfortheacquisitionofneurogenicpotentialoffloorplatecells[10]asshownbytheexpressionofpan-neuronaltranscriptionfactorNgn2.
Inaddition,arecentstudydemonstratedthatthecharacteristicDAneurontranscriptionfactorLmx1aisimportantfortheappropriateonsetofneurogenesisfromthemidbrainfloorplatecells,whereastherelatedtranscriptionfactorLmx1bisselectivelyrequiredforthegenerationofDAneuronsfrommorelateralWnt1-expressingprogenitors[11].
Tofurtherdelineatethespatialandtemporalcontributionofdistinctdopamineneuronprogenitorpopulations,itwouldbeinterestingtodeterminetheearlyandlatefatesofLmx1a-,Wnt1-andCorin-expressingprogenitorcellsandsubpopulationsofthese,usingmousestrainswithCrerecombinaseunderthecontrolofvariouspromoters.
ThestudybyBlaessetal.
[4]clearlyshowsthattheabilitytomarkdifferentcelllineagesintheventralmidbrainwillbevaluableforthegenerationofamorecomprehensivelineagemapthatwillalsohelptolinkmolecularfeaturesandphenotypesindifferentmousemutantstomechanismsthatareessentialforDAneuronsubtypedevelopment.
Importantly,suchstudieswillalsobeinstrumentalinfurthereffortstoeffectivelygeneratespecifictypesofclinicallyimportantDAneuronsfromstemcells.
AcknowledgementsWeacknowledgefundingfromtheEuropeanCommunity'sseventhframeworkprogrammeNeuroStemCellandmdDANEURODEV,andfromVetenskapsrdetviasupporttotheLinnéCenterforDevelopmentalBiologyandRegenerativeMedicine.
Authordetails1LudwigInstituteforCancerResearchLtd,Box240,17177Stockholm,Sweden.
2DepartmentofCellandMolecularBiology,KarolinskaInstitute,17177Stockholm,SwedenPublished:19July2011References1.
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Figure1.
Acquisitionofneurogenicpotentialinmidbrainfloorplatecells.
Fromanalysisofgeneexpression,themidbrainDAneuronprogenitordomaincanbesubdividedintomedial(DAM)andlateral(DAL)domains.
Left,atearlyembryonicstages,medialDAprogenitorcellsresemblefloorplatecellsexpressinghighlevelsofShh(palegray).
Right,downregulationofShh(stripedpalegrey)inthemedialprogenitordomainatlaterstagesinembryogenesispromotesneurogenesisfromthemedialprogenitordomain.
PanmanandPerlmannBMCBiology2011,9:51http://www.
biomedcentral.
com/1741-7007/9/51doi:10.
1186/1741-7007-9-51Citethisarticleas:PanmanL,PerlmannT:Tracinglineagestouncoverneuronalidentity.
BMCBiology2011,9:51.
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