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© 2015.PublishedbyTheCompanyofBiologistsLtd|JournalExperimentalBiology(2015)218,637-645doi:10.1242/jeb.109108 *Author ([email protected]) for correspondence San Diego, California La Jolla, CA92093-0202,USA. of ,Marine BiologyResearch Division,ScrippsInstitution of University systems havefocusedonthe possible contributionofthelarval or acombinationofboth. ancestral deuterostomehadalongitudinalnervecordor net aresoverydifferent, ithasbeencontroversialwhetherthe Because thenervoussystemsofechinoderms, and sister groupoftunicatesplusvertebrates bootstrap supportandcephalochordatesplusAmbulacrariaas the asthesistergroupofAmbulacrariawith high However, arecentanalysisbasedon586 nucleargenesplaces and Hedges,2005;Delsucetal.,2008; analyses, Ambulacrariaarethesistergroupofchordates(Blair and hemichordatesaredeuterostomes.Inmostphylogenetic nervous systems.However, thereisnoquestion thatechinoderms unclear whetheritisatallrelevanttotheevolutionofdeuterostome number ofancestralfeatures( simple bodyplanwithanervenetandisthoughttohavelost (reviewedin Alternatively, theXenocoelomorphahavebeenplacedbasalto as theXenocoelomorpha–sistergroupofAmbulacraria. either basallyinthedeuterostomesortogetherwithacoelflatworms hemichordates). TheenigmaticXenoturbellidahasbeenplaced and cephalochordates)theAmbulacraria( includeatleasttheChordata(, , Nervoussystemevolution KEY WORDS:,Deuterostomes,, ago, thatatruecentralizednervoussystemwaslostinhemichordates. compatible withthescenario,suggestedbyDawydoff over65 apparent lossofthisoppositioninhemichordatesis,therefore, and Nodalpositionstheciliarybandregulatesitsextent.The systems. Similarly, inechinodermlarvae,oppositionbetweenBMP partitioning oftheectodermintocentralandperipheralnervous proteins, bonemorphogeneticprotein(BMP)andNodal,regulates cord.Inchordates,oppositionbytwosecretedsignaling one ornoneofthetwonervecordsishomologoustochordate system. Forhemichordates,opinionisdividedastowhethereither not likelytobeevolutionarilyrelatedthechordatecentralnervous and abrain.A furthercomplicationisthatechinodermnervecordsare Chordata. Noneofthesegroupshasasinglelongitudinalnervecord echinoderm (),whichisasistergroupofthe basal deuterostomesorasasistergrouptothehemichordate/ nemertodermatids), whichhasbeenplacedeitherasbasalbilaterians, Xenocoelomorpha (Xenoturbellids,acoelflatworms, been complicatedbytheambiguousphylogeneticpositionof Understanding theevolutionofdeuterostomenervoussystemshas Linda Z.Holland* ofbasaldeuterostomenervoussystems REVIEW Introduction ABSTRACT Several schemesfortheevolution ofdeuterostomenervous Achatz etal.,2013). Philippe etal.,2011 Edgecombe etal.,2011). (Moroz etal.,2014). ). Therefore,itis has avery

ancestor haddirectdevelopment(Raf development, someresearchersmaintainthatthedeuterostome vertebrates. Becauseofthesedifferences inthemodeof the larvalnervoussysteminadultasdocephalochordates and with lossofmostthenervecord,basalappendicularians retain Although theascidiantadpoleundergoes adrasticmetamorphosis tunicates andvertebrates)typicallyhavedirectdevelopment. 2009). isbasalfortheAmbulacraria( to larvaeofechinodermshasledthesuggestionthatapelagic the resemblanceoftornarialarvaenteropneusthemichordates hemichordate ancestorhaddirectorindirectdevelopment.However, groups isbasal.Therefore,itimpossibletoknowwhetherthe Torquaratoridae, butotherwisefailstoresolvewhichofthefive development. PhylogeneticanalysisgroupsPtychoderidaeand three haveindirectdevelopmentandthelastdirect , RhabdopleuridaeandCephalodiscidie.Thefirst hemichordates: Torquaratoridae, Ptychoderidae,Spengelidae, be homologoustothechordatenervecord.Therearesixfamiliesof one ortheothernervecordofhemichordateshasbeenproposedto but thereisnodiscretebrainsuchasthatinchordates.Traditionally 4,5).Thecollarnervecordundergoes , (Figs both dorsalandventralnervecordsplusarelativelyneurogenic numerous ectodermalsensorycells. 2007; Hoekstraetal.,2012 are derivedfromectodermand interconnected ( inseacucumbershaveindicatedthatbothsystems separate; however, fine-structuralstudiesandhistochemistryof is thehyponeuralsystem.Thesetwosystemswerethoughttobe ectonerual compartment,whereastheinnerlayerofnervecords The nerveringandtheouterpartsofcordbelongto circumoral nerveringplusfiveradialcords echinoids andholothurians.Adultechinodermshaveincommona Within theechinoderms,crinoidsarebasaltoophiuroids,asteroids, direct developmenthasevolvedindependentlyinseverallineages. echinoids) haveindirectdevelopmentwithpelagiclarvae,although echinoderms (,holothurians,asteroids,ophiuroidsand 1,2).Allfiveclassesof nervous systemtothatoftheadult(Figs Garstang, three evolutionary linescamefromthis ancestor. Oneline al., 1995),butnotwidelyaccepted (Slyetal.,2003).Accordingto an echinodermlarvawasrevived by 1928). Evenso,theideathat ancestraldeuterostomeresembled 1),althoughhelater changed hismind echinoderms (Fig. ancestorresembled theauricularialarvaofholothurian Garstang (Garstang,1894) engendered larva-firsttheoriesofnervoussystemevolution. that theancestraldeuterostomewasapelagic,larval-likeadult, has The ideathatancestraldeuterostomeshadapelagiclarvaor even nervous systems nervous deuterostome theevolution of theoriesof Larva-first Unlike echinodermsandhemichordates,chordates(amphioxus, In contrast,thenervoussystemsofadulthemichordatesconsist ). Moreover, Echinodermsalsohave initially proposedthatadults of the Amemiya etal.,2005;Nielsen, f, 2008;Northcutt,2005). Davidson etal.(Davidson Fg 2,Fig.3C). (Fig. Mashanov etal., (Garstang, 637

The Journal of Experimental 638 speculated that ‘A primitive Chordatetadpolemay wellhavearisen the marginal ciliatedbandsofthetunicateendostyle.Further, he The adoralciliatedbandevolved intotheperipharyngealbandsand became enlarged andturnedintotheopticvesiclesofvertebrates. 1B).Thepre-oralpits the blastopore(neurentericcanal) (Fig. which wasinternallyciliatedand communicatedwiththegutnear sides fusedinthedorsalmidline. Astheyfused,acanalremained, ancestor asthecircumoralnerveringmigrateddorsallyand two become thecollarnervecord. oral andpost-oralbands.Theciliatedbandfused to lateral halvesofthecircumoralciliatedbandweredividedinto pre- evolution ofenteropneustsfromthishypotheticalancestor, the echinoderms, butevolvedintophotoreceptorsinchordates.In the this hypotheticalancestor. Thepre-oralsenseorgans disappeared in adult echinodermsarosebyventralmigrationofthenerve-ring of the circumoralciliatedring.Thecircumesophagealnervering of (CNS)wasanovalnerveringdirectlyunderlying hemichordates. Therewasalsoanadoralciliatedband.Thecentral anterior pitssimilartotheeyespotsinsometornarialarvaeof looping aroundthemouthandaposterioranus.Thereweretwo 1).Thiscommonancestorwascharacterizedbyaciliaryband (Fig. evolved intohemichordatesandthethirdlinechordates was proposedtoevolveintomodernechinoderms,asecondline nervous systemevolvedbyfusionoftheciliarybands(green). to chordatesbyneoteny Garstangs, theprotochordate-typelarvaofasessileascidianthengaverise (B) Thisdipleurulalarvagaverisetoprotochordatelarvae.Intheviewof bipinnaria, pluteus)arethoughttohavearisenfromadipleurula-typelarva. (A) Thetornarialarvaofhemichordatesandechinodermlarvae(auricularia, Fig. REVIEW Garstang envisionedthatchordatesevolvedfromthislarva-like

.A ‘larva-first’ schemeproposed 1. B A Auricularia/ dipleurula Tornaria (Garstang andGarstang, Dipleurula Early protochordatelarva ieDorsal Side by Garstang andGarstang. Photoreceptor chord Noto- Endo- style 1926). Thechordate Auricularia Bipinnaria Pluteus has beenseriouslyconsidered from anancestorthatresembledauricularialarva(thedipleurula) echinoderms, enteropneusthemichordatesandchordatesevolved Garstang andGarstang,1926). Garstang hadseriousdoubtsabout recapitulation ( roots intheideathatontogenyrecapitulatesphylogeny. However, further developmentofearlylarvalcharacters.Thistheoryhadits hemichordates, andtheendostyleneuralcanalresultedfrom from adultpterobranchancestors,whicharesessilecolonial 1928). Heargued thatthechordategillslitsandnotochordcame and apicalsense-organs beingrolledup as aneuralcanal(Garstang, withthecircumoralbandandassociatednervoussystem an increaseinyolkresultedthelarvaebeinghatchedasmuscular closer parallelismoneithersideofthedorsalmid-line.Somehow, circumoral bandanditsunderlyingnervetractwerebroughtinto elongating andbecomingmuscular. Thelateralhalvesofthe Garstang, aprotochordatelarvaarosefromthisauriculaby predecessor oftheperipharyngealbandandendostyle.Accordingto medullary folds,andtheadoralbandwithitsventralloopas underlying nervoussystemwereregardedaspredecessorsofthe of undulatingfromsidetoside’.Thecircumoralbandandits from anelongatedAuricularia-likelarvawhichacquiredthepower dl Fg 2)( adult (Fig. larva withanapicalnervoussystem, whichiscarriedoverintothe group echinoderm)withalongitudinal nervecordandapelagic end (Popodietal.,1994). ancestral nervecordduplicated fivetimesandformedaringatone 3)andthethirdthat with theendsremainingattached (Fig. was formedbysplittingofalongitudinalnervecorddownthecenter ancestral nervecord.Thesecondargues thatacircularnervecord and circumoralnerves.Oneproposesthecircularizationof an inspiredthreeschemesforevolutionoftheechinoderm radial hindbrain andspinalcordofvertebrates,cephalochordates and The discoverythat evolution of deuterostome nervous systems nervous deuterostome evolution of Genes anddevelopment have several inspired ideason persisted asalarva( evolved intoadultbilateriansandtheformerbodyplan an echinoidlarva.AtsomepointpriortotheCambrian,thesecells adult developed‘set-asidecells’,notunliketherudimentof Davidson andcolleagues.Accordingtothisscheme,larva-like of deuterostomes,andinfactallbilaterians,wasproposedby proceed’. now extinctgroupsoforganisms anditisnotatallclearhowto has notchanged.Itisoneofrecovering…someunderstanding about thetruenatureofancestralforms.Theessentialproblem the numberofviablehypotheses,butlesssoingeneratingnewideas molecular datahas(sic)sofarbeeneffective intermsofreducing leading toadvancedchordates’.Moreover, Lacallinotedthat‘the candidates tobetransitionalformsinanyevolutionaryscenario molecular dataandconcluded‘dipleurula-typelarvaearepoor modifications of Lacalli (Lacalli,2010) the adultstageofechinodermsandhemichordates.Morerecently, suffers fromthelackofpersistencelarvalnervoussysteminto 2003). the lifehistoryofadirectdevel also gavewaytoideasthatthepelagiclarvawasintercalated into The theoryofWalter Garstang Other schemeshavebeenproposed thatinvolveanancestor(stem A variationonthethemeofanechinoderm larva-likeancestor The JournalofExperimentalBiology(2015)doi:10.1242/jeb.109108 Burke, 2011). oe Rmr 92 togetherwithmorerecent Romer (Romer, 1972) Hox Peterson etal.,2000). genes areco-linearlyexpressedinthe reviewed Garstang’s theoryand the According tothis scheme,theradial oping bilaterianancestor(Slyetal., (Lacalli, 1994). (Garstang, 1894)that However, thistheory However, ittoo Garstang, 1922;

The Journal of Experimental Biology REVIEW (2011). united inchordates. remained separate inhemichordates,but circumoral nerveringandradialnerves. Thesetwonervoussystems nervous system.Intheechinoderm lineage, thenervecordevolvedinto ancestral Ambulacrarianandtheapical tuftevolvedintoaseparateanterior band ofadoliolarialarvagaveriseto thelongitudinalnervecordofan Fig. 2012). cords evolvedintotheradialnerves of echinoderms( had parallelfivenervecordsandananteriorbrain,these and Arendt,2013).A finalschemeisthatthedeuterostomeancestor systems fusedtoformaforebraininthebilaterianancestor(Tosches neurosecretory andthelatterinvolvesmotorcenters.Thesetwo system andablastoporalnervoussystem.Theformeris on thisthemeisthatabrainevolvedfromananteriorapicalnervous anterior concentrationofneuronsbecomingthebrain.A variation Only inthechordatesdidtwonervoussystemsunitewith the apicalnervoussystemremainsaseparateentityinadult. evolvedbyduplicationoftheancestralnervecord,whereas Antennapedia complex A B

.‘Larva-first’proposed byBurke. scheme 3. echinoderm Stem group band Ciliary Apical tuft cioemHmcodt Chordates Hemichordate Echinoderm Ancestral dipleurula Bithorax Hox2 Hox3 Hox4 Hox6 Hox7 Hox10 Hox14 Hox1 Cephalochordate C In thisscheme,theciliary cee1Scheme2 Scheme 1 After Burke Kuznetsov, nerve cord,which hasaventralneuropile,ishomologous tothatin (Kaul andStach,2010) nerve cordstothechordate cord.Incontrast,KaulandStach every otheropinionconcerning therelationshipofhemichordate is stillaviableidea,although subsequent authorshaveexpressed pterobranchs), whichprobablylost itinthecourseofevolution.This did notexistinenteropneusts (allhemichordatesexceptthe 4).HestatedthatatrueCNS,inmorphologicalsense, system (Fig. as localizedcondensationsofthesub-epidermaldiffuse nervous Dawydoff (Dawydoff, 1948) of theectodermahemichordate-likeancestor. Forexample, CNS, whichevolvedindependently, perhapsbycondensationofpart that neitherhemichordatenervecordishomologoustothechordate ventral nervecordandthechordateCNS,yetothershaveargued the chordateCNS,othershaveproposedhomologiesbetween the people havepostulatedthatthedorsalnervecordishomologous to neurogenic ectodermbutlackadiscretebrain.Therefore, some problems becausetheyhavetwonervecords,plusarelatively evolution ofthechordateCNS;however, theypresentparticular Hemichordates havefeaturedprominentlyintheoriesconcerning Casey, 2014). into theadultnervoussystemis not known(Cunninghamand appears tobetransient;whetheranyoftheneuronsareincorporated direct developinghemichordate,theembryonicnervoussystem expressed inthechordatebrain HNF6), whichisexpressedintheapicalorgan ofseaurchins,isnot al., 2010).Moreover, atleastonegene( (Nakanoetal., hemichordates, thelarvalnervoussystemdoesnotpersistduring problem thatinprotostomelarvaeandtheofechinoderms nervous systemfromalarvalhavethemajor those ofchordates.Schemesderivingallorparttheechinoderm that theechinodermnervecordsareprobablynothomologousto expressed inthecoeloms(Arenas-Menaetal.,2000).Thisindicates the developingadultnervecordofseaurchins,butareinstead abandoned whenitturnedoutthat 3)were proposed byPopodietal.(Popodial.,1994)(Fig. evolution of thechordateevolution CNS of Hemichordates have the played akey intheoriesof role Each oftheseschemeshasmajordrawbacks.The The JournalofExperimentalBiology(2015)doi:10.1242/jeb.109108 urchin CNS( sequentially expressedinthedevelopingadultsea Unfortunately fortheseschemes, the domainsof center, butnotattheends,resultinginaduplicationof scheme, theancestrallinearnervecordsplitin CNS circularizedandthetwoendsfused.Inasecond the cluster. Inonescheme,anancestrallongitudinal been rearrangedwithposteriorgenesinthemiddleof five radialnervecords(green).The (C) Echinodermshaveacircumoralnervecordand developing CNSoffliesandchordates. (A,B) Hox evolution oftheechinodermnervecords. Fig. et al.,2000).

yPpd ta.for Two schemesproposedby Popodi etal. 2. suggested thatneurulationof the collar genes areco-linearlyexpressedinthe regarded thehemichordatenervecords 2010; Eliaetal.,2009;Miyamoto Arenas-Mena etal.,1998; (Poustka etal.,2004).Evenina Hox Hox genes (Popodi genes arenotexpressedin Onecut, orthologousto Hox et al.,1994). Hox genes arenot Arenas-Mena cluster has 639

The Journal of Experimental Biology ectodermin in theanteriormostCNSchordates areexpressedintheanterior 1998). Evenso,homologsofa numberofgenesthatareexpressed many ectodermalsensorycells( they arealsoexpressedinthegeneralectoderm,whichcontains expression ofthesegenesinchordatesisnotlimitedtothe CNS; useful forinferringhomologieswiththechordateCNS,because 4). Fig. evolved independently(reviewed nerve netandthatthehemichordatechordatecords extension ofthisviewisthattheancestraldeuterostomehada nervous system(Loweetal.,2003; 640 Pax6 5).However, expressionofgenessuchasHox CNS (Fig. homologs ofsomechordategeneswithexpressionrestricted to the many genesthatmediateglobalpatterninginchordatesaswell as numerous neurons.Thelarvalectodermexpresseshomologs of three bodydivisions(proboscis,collarandtrunk)contains ectoderm, particularlyintheproboscis,mostanteriorof the net inthelarvalectodermof of thechordatenervecord. not decidewhetherthedorsalorventralnervecordishomolog was separatefromaperipheralnervoussystem.However, theycould common ancestorofchordatesandhemichordateshadaCNSthat adults ofthisspecieswasnotveryneuralandsuggestedthatthe developer who alsoexaminedthedevelopmentofnervecordsindirect of chordates. chordates andthatacentralizednervoussystemprecededtheorigin From Holland etal.(Hollandal.,2013). bilaterians. Aoccurred inthechordatelineage. dorsal-ventralinversionoccurredatthebaseofdeuterostomes.Inscenario4,dorsalventral chordates andprotostomesevolvedindependently. tonervecordsin Inscenario4,theancestralbilaterianhadaventralnervecord,whichgaverise cordsinhemichordates, . Thesenervecordsgaverisetoinbilaterians.Inscenario2,theancestralbilaterianhadanet.Nerve Fig. REVIEW et al.,2003)–and in strongly inthecollarandsomewhat posteriortothecollar(Lowe hemichordate ectoderm–very weaklyintheproboscisand Fgf8/17/18 Most recentlyLoweandco-workershavefocusedonthenerve

.Fourhypothesesforevolutionofbilaterian nervecords. 4. and In thedirect-developing kowalevskii Gbx , Dlx Nomaksteinsky etal.(Nomaksteinskyal.,2009), Urbilaterian in thehemichordateectodermarenotespecially and chordates isexpressed intheneuroectoderm, Rx S. kowalevskii. inversion among others. D/V S. kowalevskii Castro etal.,2006;Glardon Scenario 1 Scenario 3 in Holland,2003) , observedthattheectodermof Pani etal.,2012).Thelogical S. kowalevskii Otx These include is expressedinthe as beingthereal , thelarval (scenario2, Hemichordate In scenario1,thebilaterianancestorhadmultiplenervecordsratherlikeamodernacoel Chordate Hemichordate Protostome Six3/6 genes, , ambulacrarian. ancestor, as discussedbelow, wasmore likeachordatethanan common ancestorofAmbulacraria andchordatesunlessthis unlikely thattheISOandMHB organizers wereinherited from the suggest somedegreeofinheritance fromacommonancestor, itis interactions betweenthehemichordate ectodermandchordateCNS Therefore, althoughthesimilarities ingeneexpressionand 5). expressed astheyareinchordates(Panietal.,2012)(Fig. et al.,2010).InS.kowalevskii in amphioxusabutaboutthemidpoint ofthe Fezf so aswellinamphioxus.Similarly, ,thedomainsof another andhavebeenshowntopositiontheMHB;theylikely do the amphioxus andvertebratenervecords(C and similarly expressedinthehemichordateectoderm.Forexample, domains ofsomekeygenesthatpartitionthechordateCNSare not argument istantalizing,buthassomedifficulties –chiefly thatthe () invertebrates]werecarriedoverintothechordateCNS.This midbrain/hindbrain boundary[MHB,termedtheisthmicorganizer anterior neuralridge(ANR),zonalimitansintrathalamica(ZLI)and organism, thegeneticprogramspartitioningectoderminto evolved fromtheectodermofanancestralhemichordate-like vertebrate brain.TheimplicationwasthatasthechordateCNS mediated regionalizationofthehemichordateCNSand chordate CNS,theyargued thathomologousgeneticprograms claim structuralhomologybetweenthehemichordateectodermand l,21)(i.5).Invertebrates, al., 2012)(Fig. brain maybeevolutionarilyrelated. credence totheideathatproboscisectodermandchordate Williams andHolland,1996 but notinthegeneralectoderm Although Pani Urbilaterian S. kowalevskii Urbilaterian Gbx and Irx, whichmutuallyrepresseachother, abutat theISOand are expressedindomainsthatabutattheMHB/ISO The JournalofExperimentalBiology(2015)doi:10.1242/jeb.109108 ta.(aie l,21;Pn ta. 02 didnot et al.(Panial.,2010;Pani2012) ectoderm, theirdomainsbroadly inversion D/V Scenario 2 Scenario 4 ). Theseexpressionpatternslend , Otx Otx, (Tomsa andLangeland,1999; and Gbx, Gbx astro etal.,2006),butin Fezf diencephalon Chordate Hemichordate Protostome mutually repressone Chordate Hemichordate Protostome and overlap (Paniet Irx are not (Irimia Otx

The Journal of Experimental Biology REVIEW genes, suchas limitans intrathalamica(ZLI)( Fig. adult nervous system beginstodevelop fairlyearlyin neuronal differentiation inembryosof specification ofneuralcompetence,neuronaland determined 2014) of hemichordates. little isknownaboutgeneexpressioninthedevelopingnervecords cords hadevolvedindependently, therearemanycaveats.First,very ancestor ofvertebratesandAmbulacrariansthatchordatenerve kowalevskii are similarlyexpressedattheanteriortipofCNSinamphioxusandvertebrates,endectoderm organizer. Thesegenesarecomparablyexpressedinamphioxus,butnottheectodermof amphioxus (Branchiostomafloridae expressed atthecollar–trunkboundary(CTB)in and Gbx (Miyamoto etal.,2010).Asin into theadulteventhough gut,mouthandanusdocarryover antibody showedthatthelarval nervoussystemdoesnotcarryover together withlabellingofallneurons withananti-synaptogamin hemichordate, skin isnon-neural’.Moreover, inanindirectlydeveloping (Bullock, 1945) larval ectodermalnervoussystemin be vitaltoanunderstandingoftheevolutionarysignificance the neurons inthenervecordswasnotstudied.Suchinformationwould nerve cordsoradeathoftheectodermalneuronsandbirth new true reorganization involving ectodermalneuronsmigratingintothe nervous system(CunninghamandCasey, 2014 transient andreorganizes before hatching,intothecentralizedadult that thediffuse embryonic nervous systemof expressed athighlevelsintheproboscisectoderm.Theyconcluded development proceeded,althoughthesegenescontinued to be and becameincreasinglyrestrictedtothenervecords as of thesegeneswasrelativelybroadintheectodermearlyembryos collar andproboscis)aredemarcated(72 gastrula stage(24 While theseinterpretationssuggestedthatthemodern

Sfrp1/5 Six3/6 Dlx Fgf8/17/18 FoxG1 Rx Hh Pax6 Fng Pax2/5/8 Wnt1 En Wnt8 Gli .Expressionofanterior–posteriorpatterning genesintheectodermofhemichordate 5. Gbx Otx Fezf IrxB (the isthmicorganizer, ISO)invertebrates. AP Expression differs fromchordates larva mightprovideaproxyforthelastcommon Expression unknown Wnt8, aresimilarlyexpressedinthe simodensis,monitoringofapoptosis noted, ‘thegreaterpartoftheadultenteropneust

h) tothestagewhenthreebodyregions(trunk, Cunningham andCasey(CunninghamCasey, expression ofseveralgenesthatareinvolvedin PCB Rodríguez-Seguel etal.,2009), CTB S. kowalevskii ) (middle)andagenericvertebrate(right). S. kowaleveskii

h). Ingeneral,expression S. kowalevskii S. kowalevskii, Sfrp1/2/5 Six3/6 Dlx Fgf8/17/18 FoxG1 Rx Hh Pax6 Lfng Pax2/5/8 Wnt1 En Wnt8 Gli , inB.simodensisthe S. kowalevskii ). Whetherthisisa Gbx Otx Fezf IrxB ANR S. kowalevskii Not expressedinCNS whereas oppositionbetween ZLI . AsBullock at theboundarybetweenfezfandIrxinamphioxus(theZLI) MHB from the ectoderm andthechordateCNS,whereasothers,suchas S. is amphioxus, opposition betweenNodalandBMP signaling regulates preventing bindingtotheirreceptors ( opposition. Ithasbeenreported thattheyphysicallyinteract, through different, butrelatedtransmembranereceptorsand actin secreted signalingproteinsin the TGF of thelevelsNodalandbone morphogeneticprotein(BMP),two the cephalochordate cord evolved. that theCNSbecamereducedinhemichordatesandasecond nerve bilaterian hadacentralnervoussystemwithbrain,thenitfollows Hirth, 2013b;Tomer etal.,2010).Ifitistruethattheancestral sophisticated brain( suggest thattheancestralbilaterianhadaCNSwith fairly anddeuterostomeshaveledsomeresearchers to tunicates). Similarpatternsofgeneexpressioninnervecords of (placodes invertebrates;sensorycellscephalochordates and with abrainaswellvarietyofectodermalnervousstructures nerve cordinanamphioxus-likeancestor. ChordateshaveaCNS It isvirtuallycertainthatvertebratenervecordsevolvedfromthe single-cell resolution,wouldbehighlyvaluable. genes (suchasVChat, determining theexpressionofawiderangeneuronal-specific development ofadulthemichordatenervoussystems,including evolution ofchordatecentralnervoussystems.Thoroughstudies is morerelevantthanthelarvalsystemtoanunderstandingof raise thepossibilitythatadultnervoussystemofhemichordates embryogenesis andiscompletedintheyoungadults.Thesestudies systems A novel scenariofor hemichordate evolution nervous of In vertebrates, A clueastohowthismighthavehappenedliesinexperiments Otx S. kowalevskii and Gbx The JournalofExperimentalBiology(2015)doi:10.1242/jeb.109108 Sfrp1 Six3/6 Dlx Fgf8 FoxG1 Rx Hh Pax6 Lfng Pax2 Wnt1 En Wnt8 Gli Irx Gbx Otx Fezf IrxB ANR Saccoglossus kowalevskii and Fezf,whichopposeeachotherdefinethezona positions themidbrain–hindbrainboundaryoristhmic ZLI floridae Strausfeld andHirth,2013a; . Genesthatspecifytheanteriorneuralridge(ANR) ISO GAD, etc.),togetherwithsectionsgiving

Wnt1 S. kowalevskii. β Haramoto etal.,2006).In superfamily. Theysignal (left) andintheCNSof and engrailed involving manipulation Strausfeldand Some other are 641 Otx

The Journal of Experimental Biology ectoderm and (E,F) Additionofactivineliminatestheneuraltubeandconvertsentireectodermtoneurectoderm. Otx neurectoderm andenlargestheforebrainregion.(A,B)Controlembryosatneurulastageshowingexpressionof ectodermal sensorycells.(A–H)10 642 forms (Molina et al.,2013).This become ciliaryband.IfBMP2/4 isreduced,anectopicciliaryband ventral fate;reducedNodalsignaling causesmostectodermto Upregulation ofNodalsignaling shiftsmostoftheectodermtoa dorso–ventral polarityandthe positionoftheciliaryband. BMP2/4, whichmutuallyrepress oneanother, establishboth 2010; Luetal.,2012). elav forms, butthenumberofectodermalsensoryneuronsexpressing addition ofBMP2/4isdelayeduntilthemid-gastrulastage, CNS 6)(Onaietal.,2010;Yu etal.,2007).However, if CNS (Fig. eliminating alldorsalstructures,includingtheheadandentire whereas BMP2/4signalingventral-posteriorizesembryos, converting alltheectodermintoneuroectoderm(askin-brain), anteriorizes amphioxusembryos,eliminatingtheneuraltube and Upregulation ofNodalsignalingattheblastulastagedorso- of manipulatingtheamountNodalandBMP arestagespecific. axial patterninginearlydevelopme is expressedindorsalmesodermandoverlyingneuralplate.(J) BMP4toamphioxusembryosattheblastulastagehasoppositeeffect Controlembryos.(I) asadditionof activinatthesamestage.(I–K) Fig. REVIEW (arrowheads) isincreasedandtheirpositiondorsalized.g,gut;n,neuralplateortube;nc,;s,. gastrula stage,theneuralplate(arrows)isstillspecifiedasshownbyexpressionofpan-neuralmarker BMP4proteinisdelayeduntilthe around theblastopore.(O)Atearlylarvalstage,headandalldorsalstructuresareeliminated.(L,P)Whenadditionof Addition ofzebrafishBMP4atthegastrulastageeliminatesalldorsalstructures. tipofthelarva.(M–O) early larvalstage,thegutendoderm(g)expressesalkalinephosphatase.Arrowheadindicatestail;asteriskanterior ratio ofthesecretedTGFβ 2010). I–K,M–OfromYual. (Yuet etal.,2007). L,P from Similarly, inseaurchinlarvae,thesecretedproteinsNodaland

in thehindbrainandspinalcord.(C,D)Cross-sectionsthroughneurulaeatlevelsindicatedA toroundup. andB.Theneuraltubehasbegun .A switchfromacentralnervoussystemto‘skinbrain’ iseffectedinthebasalchordateamphioxus( 6. is increasedandtheyarepositioned Wnt3 throughout theentireposteriorectoderm.(G,H)CrosssectionsthroughlevelsindicatedinEandF. (I–K,M–O)Additionof250

zfBMP4 Control Activin Control EF proteins,NodalandBMP fromtheearlyblastula. AB N P MNO IJ L K G G C hri rcyr laiepopaaeHu/elav Alkalinephosphatase Brachyury Chordin C

ng at blastula ml Otx suggests thatNodal vsBMP isa nt (Onaietal.,2010).Theeffects − at blastula 1 activinappliedtoamphioxusembryosattheearlyblastulastageconvertsentireectoderm more dorsally(Onaietal., at blastula at blastula Lu etal.(Lual.,2012). Wnt 3 Brachyury D D H H is expressedinthedevelopingnotochordandaroundblastopore.(K)At Chordin Changing thisratioatthegastrulastage,affects developmentofthe upregulated expressionofthesensoryneuronmarker expression oftheneuraldifferentiation marker protrochophore andearlytrochophorelarva),didnotchange BMP added at24hourspostfertilization(betweenthe ancestral bilaterian(Fig. opposition intheregulationofneuralterritorieswaspresent the how manyectodermalcellswillbeallocatedtoeachcompartment. to CNSorectodermalsensorycellsandforregulatingwhere and fundamental mechanismindeuterostomesforallocationofectoderm signaling would haveaneffect ontheCNS and/orperipheral is expressedindevelopmentand whetherupregulationofNodal (gb|ELT90528.1), anditwouldbemostinterestingtoknowhow has beendescribedfrom theannelid was presentinthebilaterianancestor. Anapparent and supportstheideathatBMP regulation ofneuronalsubtypes comparable toadditionofBMP atthe lategastrulainamphioxus of cellsexpressingthegene lateral peripheralnervoussystemanlageandexpandedthenumber CD GH In fact,itispossiblethataroleforNodalandBMP actingin at blastula n g is nolongerexpressedand n Otx The JournalofExperimentalBiology(2015)doi:10.1242/jeb.109108 nc? nc s Otx is expressedthroughouttheexpandedanterior Hu/elav

7). Intheannelid n , butthenumberofectodermalsensorycells Wnt 3 Wnt3 brachyury at gastrula (Denes etal.,2007).Thisis in theforebrainandendoderm A–H from Onai et A–H fromOnai g nc s expression islimitedtotissue Platynereis dumerilii elav Capitella telata al. (Onaietal., Nodal ) byalteringthe , butstrongly

ng ath sequence ml Chordin − 1 in the ,

The Journal of Experimental Biology 2014), strengthens thenotionthatcommon ancestorof cephalochordates assistergroup ofthe Ambulacraria ( in connectionwiththectenophore genomepaperplaced surprising resultthatthreeof fourphylogenetictreespublished out toholdforprotostomes, inparticular. Moreover, the for regulationofneuralterritories wouldbestrengthenedifitturns the ideathatNodalvsBMP isafundamental bilaterianmechanism evolve inhemichordates.Althoughthisscenarioispurespeculation, of BMP andNodalcouldthenhaveallowedasecondnervecordto the brainbecomingspreadoverproboscisectoderm.Decoupling Ambulacraria mighthavebecomereducedinhemichordates, with the brain–incommonancestorofcephalochordates and territories waslostinhemichordates.Ifso,theCNS–particular antagonistic roleofBMP vsNodalinspecificationofneuronal (Lowe etal.,2006;Wlizla, kowalevskii appear toaffect thenumber ofbasiepithelialneuronsin Nodal (Grande andPatel,2009). in protostomesandmediatesleft–rightpatterning,aschordates However, studiesinmolluscsshowedthat it wasassumedthat REVIEW the attentionitdeservesbecauseas nervous system.Nodalsignalinginprotostomeshasnotreceived expression isunknown,whereasarthropodshavelost controlling centralizationoftheCNStoaroleinposteriorpatterning.BMPAnnelids havea isexpresseddorsallyin annelidsandarthropods. situation inseaurchins,butdiffers fromthatinhemichordates,suggestingtheroleofNodal may havechangedinhemicho amphioxus, oppositionbetweenNodalandBMP tothe signalingregulatesdevelopmentofaCNSand ectodermal sensoryneurons.Thisiscomparable are inverteddorsal–ventrallywithrespecttothehypotheticalbilaterianancestor, Inthebasalchordate annelids,,hemichordatesandechinoderms. (Wlizla, 2011). UpregulationofNodalsignalingposteriorizesembryos.ExcessBMP hasnoeffect neurons. Chordates onthenumberorpositionofectodermal antagonistic NodalandBMP expressionpositionstheciliaryband.Inhemichordate having aventralnervecord,thepositionofwhichisregulatedbyoppositiondorsalBMP Inseaurchinlarvae, signaling andventralNodalsignaling. Fig. In contrast,in

.Schemeforevolutionofcentralnervous systemsthroughoppositionofNodalandBMPs.Thehypotheticalbilaterianancestorisenvisionedas 7. is expressedposteriorly. Moreover, excessBMP doesnot , andNodalappearstoposteriorizeonlytheectoderm S. kowalevskii Arthropods Nodal Dpp/BMP , although was specificfordeuterostomes. 2011). Thissuggeststhatthe Drosophila lost Nodal gene BMP Nodal Nodal? is expresseddorsally, Nodal BMP lacks a Annelids is indeedpresent . Moroz etal., Nodal ancestor bilaterian Hypothetical gene, S. Nodal to nervecordsinprotostomesanddeuterostomes(Fig. acoel-like ancestralbilaterianmighthavegivenriseindependently proposed (Hejnoletal.,2009),then Xenocoelomorpha). Iftheyarebasaltobilateriansashas been acoel ,xenoturbellidsandnemertodermatids (the has beencomplicatedbytheuncertainphylogeneticpositions of Understanding hownervoussystemsaroseindeuterostomes ancestral bilaterianhadaCNSwouldbeconsiderablystrengthened. cephalochordate thanahemichordate.Ifso,thetheorythat Ambulacraria andChordatajustmightbemorelikea basiepithelial nerve netisreallytheequivalent oftheperipheral ectoderm. Indeed,ithasbeen suggestedthatthehemichordate (CNS orciliaryband)andless-neural (containingsensoryneurons) BMP regulatescompartmentalization oftheectodermintoneural the cephalochordateamphioxus andinechinodermlarvae,Nodalvs systems maylieinoppositionbetween NodalandBMP proteins.In evolution. secondarily simplifiedandirrelevantfordiscussionsof CNS 2013a). Ifso, nerve cordandbrain(De et al.,2011), if theyarebasalinthedeuterostomes Conclusions Chordates The keytounderstandingevolution ofdeuterostomenervous Nodal BMP S. kowalevskii The JournalofExperimentalBiology(2015)doi:10.1242/jeb.109108 the ancestralurbilaterianmighthavehadalongitudinal Echinoderms then nervoussystemsinXenocoelomorphawouldbe BMP , BMP isexpresseddorsallyandNodalposteriorly Hemichordates Ventral BMP Vegetal pole pole Robertis, 2008;StrausfeldandHirth, Ciliary band the multiplenervecordsofan Dorsal (Bourlat etal.,2006;Philippe rdates, shiftingfromarolein Nodal Nodal

4). However, gene, but 643

The Journal of Experimental Biology 644 Garstang Garstang Elia Edgecombe Denes Delsuc De Robertis Dawydoff Davidson Cunningham Castro Burke Bullock Bourlat Blair Arenas-Mena Arenas-Mena Amemiya Achatz [NSF/IOS-1353688]. research iscurrentlysupportedbyagrantfromtheNationalScienceFoundation The authorhadnoextramuralfundingduringwritingofthisreview, althoughher The authordeclaresnocompetingorfinancialinterests. manuscript. the NationalScienceFoundation(NSF).N.D.Hollandcriticallyread Florida atStAugustine,Florida,USA,May13–15,2014,whichwassupportedby first nervoussystemsII’ organizedattheWhitneyLaboratoryofUniversity This reviewwaswritteninconjunctionwithatalkpresentedatthe‘Evolutionof ancestral bilaterian. conserved inannelidsandwas,therefore,probablypresentthe establishing positionandidentityoftheneuralectodermis of thistheorywouldbetodetermineiftheroleNodalvsBMP in the decouplingofBMP andNodalfunctions ancestor wouldhavepartiallydegeneratedinhemichordatesdueto In thatcase,awell-developedCNSincephalochordate-like deuterostome withalongitudinalnervecordwouldbestrengthened. 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