POMC Is Mainly Peptide (Nakanishi Et Al

Journal of Molecular Endocrinology 10.1530/JME-15-0288 and JoseMiguel Cerdá-Reverter produced in the pituitary gland and its posttranslational produced in the pituitary 1979)(Fig. 1 ). POMC is mainly peptide (Nakanishi et al. latter alsoincludesβ-endorphin,anendogenous opioid middle of the as the N-terminal sequence of ACTH, and by acoresequenceHFRW: γ-MSHinpro- γ-MSH, Each domaincontainsoneMSHpeptideeasilyidentified and theC-terminalβ-lipotropin (Eipper & ). Mains 1980 (MSH), thecentraladrenocorticotropichormone(ACTH), the N-terminalpro-γ-melanocyte-stimulatinghormone In tetrapods,thisprecursorintegratesthreemaindomains: melanocortins among other biologically active peptides. precursor whoseposttranslationalprocessingyieldsthe Proopiomelanocortin (POMC)geneencodesaprotein Introduction evolutionary hypothesesproposedforPOMCevolution. emerged concerningthesequencedgenomes.Inthisarticle,wesummarizedifferent and putativecoevolutionaryevents.Controversialconflictinghypotheseshave underwent complexevolutionaryprocesses,includinginternaltandemduplications both PNOCandPOMCseemtohavearisenduealocalduplicationevent. prodynorphin (PDYN),andnociceptin/proorphanin(PNOC)aswellPOMC,although the vertebrategenometogeneratefourdifferent precursors:proenkephalin(PENK), core sequences(FGGF).Thisgenefamilydiversifiedduringearlytetraploidizationsof family, whoseprecursorsinclude eitheropioid(YGGF)ortheorphanin/nociceptin hormone (ACTH),andβ hormones, includingmelanocyte-stimulatinghormones(MSHs),adrenocorticotropic Proopiomelanocortin (POMC)isacomplexprecursorthatcomprisesseveralpeptidic Abstract 3 2 1 Sandra Navarro POMC: anevolutionary perspective 60 YEARSOFPOMC de Bioloxía,UniversidadeVigo,Spain Investigaciones Científicas(IIM-CSIC),Vigo,Spain Acuicultura deTorre delaSal(IATS-CSIC), Castellón,Spain Laboratorio deFisioloxíaAnimal,DepartamentoBioloxíaFuncionaleCienciasdaSaúde,Facultade Aquatic MolecularPathobiologyGroup,InstitutodeInvestigacionesMarinas,ConsejoSuperior Control ofFoodIntakeGroup,DepartmentFishPhysiologyandBiotechnology, Institutode http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0288 Thematic Review β-lipotropin domain. The C-terminal of the 1 , Lucia Soletto -endorphin. POMCbelongstotheopioid/orphaningene 1 , Sara Puchol s

1 navarro © 2016SocietyforEndocrinology Published byBioscientifica Ltd. andothers Printed inGreat Britain β-MSH in the 1 , Josep Rotllant α-MSH e al.2002, (Dores et sequence, YGGF, orthePNOCcoresequence,FGGF in whichallgenesencode atleastoneopioidcore POMC genebelongstotheopioid/orphanin genefamily, Evolution ofopioid/orphanin family (Castro &Morrison1997). β-endorphin inthemelanotrophsofparsintermedia the cleavagebyPC1andPC2producesα-MSH in thecorticotrophsofanteriorpituitary, whereas 1 (PC1)generatespro-γ-MSH,ACTH,andβ-lipotropin proteolytic cleavageofPOMCbyprohormoneconvertase processing occursinatissue-specificmanner. The POMC evolution The GuestEditorsfor thissectionwereAdrianClarkandPhilip Lowry. This paperispartofa thematicreviewsectionon60Years ofPOMC. 2 , JoseLuis Soengas Dores &Lecaude2005).Thegene 3

Downloaded fromBioscientifica.com at10/01/202103:01:16AM f f f f f f f f f f f f (2016) Endocrinology Journal ofMolecular [email protected] Email to JMCerdá-Reverter should beaddressed Correspondence 56 evolution opioid β-endorphin ACTH MSH proopiomelanocortin Key Words : 4 56 56, T113–T118

: 4

T113–T118

via freeaccess Journal of Molecular Endocrinology are located on chromosomes 20 and 2, respectively, whereas vertebrate genome.Inthehuman genome,PDYNandPOMC peptide genes are only located on three chromosomes of the (Sundström et al.2008). duplication occurredintheancestorofteleostfish(3R) the vertebrategenome(1Rand2R),‘extra’ grew concomitantlywiththetwoduplicationrounds of (amphioxus andtunicates).Subsequently, the genefamily been describedinthegenomeofcephalochordates genes normelanocortinreceptor-relatedhave (Dores &Baron2011).Neitheropioid/orphanin-related that probablyappearedearlyinthecordateevolution are allderivedfromacommonancestralopioidgene al.2015).Theseunifyingfactorssuggestthatthey et after the regionencoding the signal peptide (Larhammar addition, allfamilygenesexhibitasingleintronshortly in PENK,PDYN,andPNOC,onlyfourPOMC.In N-terminal regionofthemolecule.Sixresiduesarefound sixcysteineresiduesatthe retained asetofconserved among themselvesandbetweenspecies,buttheyallhave motif, membersofthepeptidefamilydiffersubstantially as (PDYN), andnociceptin/proorphaninPNOCaswell family includesproenkephalin(PENK),prodynorphin boxes indicateendoproteolyticcleavagesites(datafromCerdá-Reverteret al.2003). and darkgreyboxesshowMSHpeptidesendorphincore,respectively. Theboxedareademarcatesγ-MSHsegmentinspecieslacking-MSH.Black (Squalus acanthias)Amemiyaet al.1999b).WhitelettersonblackbackgroundindicatefullyconservedcysteineresiduesinallPOMCsequences.Light (Dores et al.1997),goldfishCarassiusauratus)Cerdá-Reverter2003AfricancichlidfishHaplochromisburtoniHarris2013anddogfish (Protopterus annectens)Amemiyaet al.1999a),whitesturgeonformBAcipensertransmontanus1997garLepisosteusosseus ) Alignment ofPOMCsequencesfromhuman(Homosapiens),AfricanclawedfrogformBXenopuslaevis)Deenet al.1991lungfish Figure 1 DOI: 10.1530/JME-15-0288 http://jme.endocrinology-journals.org Thematic Review Dogfis Africa Goldfi Gar Sturge Africa Africa Human Dogfis Africa Goldfi Gar Sturge Africa Africa Human Dogfis Afric Goldfi Gar Sturge Africa Africa Human POMC (Danielson&Dores1999).Besidesthiscore Synteny studies have demonstrated that all four opioid Synteny studieshavedemonstrated thatallfouropioid an cic h n cich sh on n lung n claw h n cich sh on n lung n claw h sh on n lung n claw

hlid :----MVCQCWLLVAVMAFVCIP--GFESV lid fish ed frog lid fish ed frog fish ed frog

:MLR

: :DCGP :MPRS

:----- :VLN :MFR :----- :LLE : ----- : ----- : ----- : ----- : FLN : RS : VLP : LFA : LLS : MLR : MLK : HFRWG : MMQ : MVR ----- YRMEH HLPAV PLSPA ALAPP- ALSQP IIPALE LFPSS SVW---VYSL PVWGC PVWR- PTGGC QSMWR GVRML LPEGGP CCSRS ------RGPK ----- ε-MSH FRWGKP VSQTS ALALA RDEVE DNQNA VVAVM HLFVL SLAIL SVLVV CPAWL GALLL GSAQS -QAEEE SH--NNLDM ------E-PRSDGAKPGPR----EGKRSYSMEHFRWGKPVGKKRRPVKVYPNGAE--DESAEAFPLEFKRELT C-Terminal Peptideof QMEDE EQMDP RESEE QGDNM GVLWFY SAVLM GVFIFH LCMVW LALAV AGLKMR GL ALLLQA WGPDR ------MEESE ----- AVLLQQ s

navarro EMETL GSSPR EEGLQ EEDSL EEEPM IYGT- ARSS- LCAGG © 2016SocietyforEndocrinology EPKLK TQPMQ CS---GVQSQ IG---EVQSQ ------SSQQQ ----- SM--EVRGW ---SGREQ N-Terminal Peptid FPRQD ---HELK QHRRD S-RQDDRR D-RQENKR SEVRAQ -GVHSQ -GQLRE ARSDE FTNLE ------RREDKR ----- andothers Printed inGreatBritain GKRS DKRS C C C C RRSYSMEHFRW C C DMLQE C GAQAD C WEHSQ WEHSQ WESSR LESSQ ------WEDAR WETSK ----- WDHTK ARDSS WDNSI RS --KSEEN --DIEDN SYSMEH SYSMEH AYSMEH YSMEH YSMEH YSMEH SMDND LEHSL C C C C -EEGAL GENEV C C GENDL C KSQSP C α-MSH RDLSS RDLSS ADLSS QDLTT RDLTT RDLST RQLTS KDLSN FRWGK FRWGK FRWGKP FRWGKP FRWGKP FRWGKP DIMNL EVERA δ-MSH LPEEEV LVAAE LNLQEK LNLQEK LSLQE GKPS EENILE EANILE EDGILE ESNLLE NQQDK DENILD ESNLLE APKLME KARILD PMGRKRR PVGRKRR e LEKKDRN-YRMQ LTKKNGN-YRMH VGRKRR VGRKRR VGKKRR VGRKRR KKDEG GRKRR RKDRT-YKMSH KKDGDDYKFGHFRWSVPLKDKRYGGFMKSWDER CL KDGS-YKMN KDGS-YKMH KDGS-YKMNH

C C C C C C C C IQA IQA IK IRA IQL IKS IEA VHL ACTH PIKVYP PVKVYP PIKVYT PVKVY PIKVYP PIKVYP PVKVFA P- A C C C C C C C C YRMEH complicated. Therearethree alternativescenariosforthe (1R and2R)oneeventof localduplication. seems tobetheresultoftwo complete genomeduplications 2015). Therefore,theexpansionof theopioidpeptidesystem brought togetherbyatranslocationevent(Larhammaret al. were onseparatechromosomesafter2Randthatthey we cannotexcludethepossibilitythatPNOCandPOMC softshell turtle,theyarejustaround1Mbapart.However, in severalspecies,includingteleostfish.Infact,the resulting inPNOCandPOMC.Bothgenesareclosetogether the lastopioidpeptidearosebyaneventoflocalduplication 2010; reviewed in of allteleostfishthathavebeenstudied(Sundströmet al. chromosome intheopossumaswellgenomes POMC andPNOCbecausebothgenessharethesame ancestral structureseemstoinvolvetheassociationbetween a translocationintheancestorofplacentalmammals.The PENK onhumanchromosome8apparentlyasaresultof with the chickengenome.Therefore,PNOCislocatedtogether and PENK is found on chromosome 2, whereas both chicken genomeexhibitsadifferentorganizationbecause chromosome 8hostsbothPENKandPNOCgenes.The POMC evolution NSDLT KVDLS KMDLS KPDLS RSDLT KSDLSA KVEKT MSVIQ Published byBioscientifica Ltd. PNGVE β-MSH NSFE NEVE NGVE- NGME- NGVE- SSLE HF HF HF HF FRWSG FRWG FRWGS Dating whenlocalduplication tookplaceis AESPI AESPL AESPV AETPM DETPV LESPI TEIPE RWSG RWSR RWNS RWGS is absent from PNOC occuronchromosome3.PDYNisabsentfrom ESPVY IP on chicken chromosome 3, but is found with POMC onchickenchromosome3,butisfoundwith --DESVE --EESAE --EESAE GGSSS SPPASK -EESAE -DESAE -EESAE PPAS PPKD PPKD PPKD PPKD PPKD FPGNG FPGNG FPGNG FPGNG YLGES YPGNG LSALA PGNGH EGRFP KRYGGFM KRYGGFM KRYGGFM KRYGGF KRYGGFM KRYGGF NMGPE SYPAE TLPAE AYPTE SYSPD SFPME RNGGFM HLQPP HLQPT HLQPL DEQPL HFQPPS HTEPI LKVDS MQPLS FQARR LKREAS IRRDLS MRRELA MRRDLM LRRDMP LRRELS MT MT KSWDER KSWDER KSWDER SEADRN SEDIQN SESIRK TENPRK KPWEEK AESLRN KSWDER DADAGD EDIRK E---- P--ERSQTP S--EKSQTP QLSSSE β-Endorp ). It suggests that 2015 ). It suggests that Larhammar et al. GQR-LREGDG T------GQKPLL SQKPLL SQKPLL SQKPLM YAKSHF YVMSHF YVMTHF YVMGHF YMMTHF ------PQGQLA YVMGHF SQKPLL GGGDDY DEAEGD γ-MSH γ-Lipotr LMTLFK LVTLFK NEVDYP SDLDYP MEFDYP LELDYP VDFDYP LKLDYP Downloaded fromBioscientifica.com at10/01/202103:01:16AM TLFRNV TLFKNV TLFKNV TLFKNV RSTAL HWNTF RWNKF RWDRF RWDKF ----- KFFRNI RWNKF TLFKNV DDDLLL hin IDGGSN PDGPAD NAIIKN VVETSE QGEELE NAIIKN Q------LLEEVE EPSSEE EIDLDE GRRTNG GQRMNG GRRNNT GRRNSS GRRNNE ------GKKRGN IVKDGH INKEHQ IIKDGH MIKDAY LKM------MIKDGH SVILAT opin ENQGLL DGA------TH-KKG AGEEEM EVFG AY-KKG EELG ------SVG---- TPG---- GNDG SSGS ------NTG------EKKAQS QKKGQ- EKKGQ- Joining peptide -KKD EKKGQ- LASRDK ------R------SSGGYK --SGAGQK 56 LEDAKK ------L- Q- E- --TGNKRE ------Q :32 SSKQA GSKREG FSGNKR ISESD ------: :26 :27 :22 :25 :25 :26 :26 -- 4 ------KDGKI ------GENAAL REDISN REDVSA ---LEQTE ------LKARSD ------0 ASTTLS EDEPVR 0 0 2 9 5 7 4 DGYKTP δ-MSH ------YKMT ------:19 -- :15 SI :10 YP :11 GE :11 ER :10 -- :18 - :199 V :10 A :10 :104 :21 :20 : 79 : 199 : 194 T114 POMC 8 9 5 0 1 9 8 9 6 7 8

via freeaccess

Journal of Molecular Endocrinology POMC, proopioimelanocortin(Data from Sundströmet al.2010). preproenkephalin; PDYN,preprodynorphin; PNOC,preproorphanin; but before2R(scenario2),orafter (scenario3).PENK, both PNOCandPOMCcouldtakeplace before1R(scenario1),after different scenarioshavebeensuggested.Localduplicationgenerating common ancestorleadingtoPNOCand POMCisuncertain,andthree genome andlocalduplications.Thetimingoftheduplication Proposed evolutionaryhistoriesfortheopioid/orphaninfamilyby Figure 2 existence oftwoPOMCorthologsinlampreys.Thismodel organisms, whichprovidesconsiderablesupportforthe reported anewmodelthatacceptslampreysare2R al. 2010). In fact, or twice(Sundströmet it isunknownwhethergenomelampreysdoubleone emerged beforethesecondgenomeduplicationbecause other chordates.ItisimpossibletosaythatPOMC probably occurredbeforethesplitofcyclostomesform means thattheduplicationgeneratingPNOCandPOMC 1995a,b). The fact that lampreyshave al. peptide), andaβ-endorphinsequence(Takahashi et (an whereas theproopiomelanotropin(POM)encodesMSH-B a proopiocortin (POC)geneencodesanACTHsequence, because cyclostomeshavetwoPOMC genome couldhelpsolvesuchdatingambiguities (scenario 2),orafter2R3,Fig.2).Thelamprey taken placebefore1R(scenario1),afterbut2R PNOC andPOMC.Thislocalduplicationcouldhave the timingoflocalduplicationthatgeneratedboth schemeofopioidpeptides,whichdifferin evolutionary http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0288 Thematic Review β-MSH-related sequence, and a α-MSH-related peptide), MSH-A (aβ-MSH-related s

navarro β-endorphin sequence, © 2016SocietyforEndocrinology POMC sequences andothers sequences. The Printed inGreatBritain Dores (2013) ( duplication eventsotherratherthangenome seem tobetheconsequenceoflineage-specificgene 2013),butthey latipes)(Harriset al. and medaka(Oryzias 2005), Burton’s ), mouthbrooder(Haplochromis burtoni such asbarfinflounder(Verasper al. moseri)(Takahashi et Three differentgeneshavebeenfoundinsomespecies expression andpeptidedomainsduringteleostevolution. paralogs haveexperiencedsubfunctionalizationofboth peptideregions.Thus,POMC possess well-conserved neutral evolutionintetraodontids,whereasPOMCα lacks theconsensusopioidsignalandseemstobeunder gland. the brainandweaklyinparsintermediaofpituitary gland, whereasPOMCβ rostral pars distalis and pars intermedia of the pituitary homolog ofthearcuate nucleus infish,aswellthe in thenucleuslateralistuberisofhypothalamus, have beencharacterizedinTetraodon. ( subfunctionalization hasbeendemonstratedinTetraodon al.2010,forreferences)and already (Sundströmet in all teleost fish in which the genome is sequenced its function).POMC (the sequenceofthenewcopydegeneratesandloses function oftheoriginalcopy),orpseudofunctionalization the newcopy),subfunctionalization(bothcopiesshare new genecopiescanexperienceneofunctionalization(by (Meyer&Vanhave oftenbeenconserved dePeer2005).These duplication round (3R), and the emerging duplicated genes POM aroseinthisspecificlampreyduplicationevent. 2013).Therefore,itispossiblethatPOCand (Mehta et al. probably alsoathirdindependentgenomeduplication al.2013)but lampreys haveundergone 2R (Smithet sequencing projecthasprovidedsoundevidencethat sequencing project.Ongoingresultsofthegenome will dependontheconclusionoflampreygenome the lampreybrain(Dores2013),butfinalcorroboration Enkephalin-like peptideshavebeencharacterizedin predicts unidentifiedPENKandPDYNgenesinlampreys. gene as both N-terminal region and carboxyterminal gene asbothN-terminal region andcarboxyterminal an MSHsequencewasinserted intothepreproendorphin precursor probably arose when aDNA segment encoding (ACTH andothermelanocortin motifs).Thiscomplex probably totheinsertionof themelanocortinsequences POMC is themostcomplexoffouropioidprecursorsdue Evolution ofPOMCstructure POMC evolution Sundström et al.2010). al.2005).Two differentPOMCorthologs de Souzaet Published byBioscientifica Ltd. The genome of teleost fish experienced a third genome The genomeofteleostfishexperiencedathird POMCβ geneshaveaβ

is expressed in the preoptic area of is expressedinthepreopticareaof duplicates have been described duplicates havebeendescribed Downloaded fromBioscientifica.com at10/01/202103:01:16AM -endorphin segment that -endorphin segmentthat POMCα 56 : 4 is expressed isexpressed T115 genes genes via freeaccess

Journal of Molecular Endocrinology and tetrapod POMCsequences(namely, α-MSH, POMC. ThepresenceofthreeMSHcoresequencesin regarding thestructureofancestralgnathostome tetraploidization isdoubtful,theregreatercertainty the organizationplanofagnathanPOMCbefore POMC precursors differs between species. Although ( arising asaresultoftetraploidizationsfromsinglegene encoding melanocortinreceptorshavealsosuggested melanocortin aroseindependentlymuchearlierasgenes cannot beexcluded that a geneencoding ACTH/ when adistinctpreproendorphingenearose.However, it the twovertebratetetraploidizationsbecauseitwasthen provided evidencethatthissegmentwasinsertedafter Dores &Baron2011). (Polypterus senegalus)Bagroskyet al . 2003);paddlefish(Polyodonspathula)Danielsonet al1999).Figure1foradditionalreferences (Data from fish, andtwotetrapodsarepresented. TheN-terminalcleavagesite(A)andtheC-terminalα-amidation(B)areboxed.Bichir Comparison ofγ-MSHsequences.The γ-MSH sequenceandtheflankedproposed endoproteolyticcleavagesitesforfiveray-finnedfish,onelobe-finned Figure 3 melanocortin copies was inserted. melanocortins oralargersegmentencodingmultiple the POMCevolutioniswhensegmentencoding melanocortin receptors.Oneofthekeyquestionsabout together withtwodifferentreceptorfamilies:opioidand ( sequences asa result of unequal crossing-over events the ancestralgenethatleadtomultiplemelanocortin it could also be the result of accumulativemutationsin an endorphinpeptideintheC-terminalregion,although cysteine residuesintheaminoterminalregionandencodes three otheropioidprepropeptides.POMCkeepsthefour peptide maintainstructural/sequenceidentitieswiththe Cortés et al.2014). Dores &Baron2011).Consequently, POMChascoevolved DOI: 10.1530/JME-15-0288 http://jme.endocrinology-journals.org Thematic Review As mentionedpreviously, thestructuralplanof γ-MSH) suggestsPOMCevolvedthroughintragenic Spiny dogfish Paddlefish Sturgeon Bichir Gar African lungfish Clawed frog γ -MSH

navarro Sundström

andothers Printed inGreatBritain

MSH/ACTH . (2010) et al β-MSH, ---EDI ---EDV ---ESLRNYVMGHFRWNKF ---EDI ---EAD ---ESI ---EDIRKYMMTHFRWDKF

A B QNYVMSHFHWNTF QNYIMKHFRWNSL QNYIMKHFRWNSL RNYAKSHFRWSTA RKIVMTHFRWNKF 1997, (Amemiya et al. only asavestigeinnon-teleostfish,includingsturgeons 1999a, fish) showsthesamethreeMSHdomains(Amemiyaet al. 1979). POMCprecursorinsarcopterygian fish(lobe-finned al. duplication ofanancestralMSHgene(Nakanishiet 1999b). This et al. duplication process seems to be unique its binding to melanocortin receptors is poor (Amemiya ACTH/α-MSH andβ-MSH,butitsfunctionisunknownas segment. Thenewδ-MSHsequenceispositionedbetween arose asduplicationfromtheβ-MSH–-endorphin domain (γ-MSH)tothePOMCstructure,whichprobably The cartilaginous lineage added a fourth melanocortin i.e. threemelanocortindomains(γ-, subsequently tetrapods,kepttheancestralorganization, Neoceratodus forsteri),coelacanth(Latimeriachalumnaeand annectensand fish, includinglungfishes(Protopterus finned fish,threestructuralplanesemerged.Lobe-finned ancestral gnathostomeintocartilaginous,ray-,andlobe- α-, andβ-MSH),and,followingthedivergenceof gnathostome exhibited three melanocortin domains (γ-, α-MSH-ACTH (Harriset al.2013)Fig.3). result ofaputativetandemduplicationthesegment described incichlidandPomacentridaespeciesasa novel melanocortinpeptide,termedδ-MSH,hasbeen al.1999b).A MSH domaintermedδ-MSH(Amemiyaet 2003).Cartilaginousfishhaveanadditionalfourth et al. present inteleosts(Salbert POMC evolution Published byBioscientifica Ltd. This suggeststhatthePOMCprecursorofancestral e al.1999). The γ-MSHdomain appears Dores et β -MSH GKK--- GQR--- GRN--- GRN--- GRR--- GRR--- GRR--- Alrubaian β Downloaded fromBioscientifica.com at10/01/202103:01:16AM -endorphin t al.1992, et . 1999),andisnot et al

56 : α-, andβ-MSH). 4 Cerdá-Reverter T116 via freeaccess

Journal of Molecular Endocrinology site isalsoabsentinbichir, sturgeon, andpaddlefish POMC precursors improbable. The C-terminal cleavage which makes γ-MSH processing and release from these and acipensiformes precursors, absent in polypteryformes dibasic pair. However, itis clear thatthiscleavagemotifis Interestingly, spinydogfishalsoexhibits thesame in thegarprecursorcanworkasadibasiccleavagesite. arginine residue.ItisnotclearwhethertheRNmotifpresent does not exhibit a basic lysine residue C-terminal to the paddlefish POMCprecursors.However, thegarsequence is stillpresentingarbutabsentbichir, sturgeon,and of theγ-MSHpeptide(Fig.3).Thisbasicarginineresidue and amidation signals alsooccurattheC-terminal region peptide (Doreset al. 1999).Bothendoproteolyticcleavage residue (K)attheN-terminalextremeofγ-MSHprocessed an argininebasicresidue(R)whilemaintainingalysine γ-MSH peptide,whichischaracterizedbythepresenceof show an endoproteolytic cleavage site just prior to the distinctive features.Lobe-finnedfishandtetrapodspecies however, theN-terminalγ-MSHdomainexhibitssome domains (γ-MSH, kept theancientorganizationalplan,i.e.threeMSH process.Therefore,chondrostean during theevolutionary of Dores andcoworkerssuggestthatthiscompletedeletion theMC3R.Experimentsduring the 1990sbyRobert at existenceofN-extendedformsmuchmoreactive the the alternativeprocessingofN-terminalregionand binding to the receptor, and by extension, it suggests It suggeststhattheN-terminalpartcouldplayarolein the specific fullagonisthasbeenunfertile(Hrubyet al. 2007). al.1993).Inaddition,thesearch forpotent Rehfuss et processed peptidearelowinanytestedspecies(Roselli- of melanocortin3receptor(MC3R),butthelevels questions ofPOMCevolution.γ-MSHisthemainligand peptide isoneofthemostintriguingandchallenging 2003).Themeaningoftheγ-MSH (Cerdá-Reverter et al. finned fishisthecompletedeletionofγ-MSHdomain (Amiiformes), andteleostfish.Theendpointinray- integratesgars(Semiontiformes),bowfin Neopterygii and sturgeonspaddlefish(Acipenseriformes),whereas lineages. Chondostreiincludesbichirs(Polypteriformes) fish that currently include Chondrostei and Neopterygii and holocephalanlineages(Amemiyaet al.1999b). presence ofthefourthMSHpeptideinbothelasmobranch the divergence of cartilaginous fish, as indicated by the lineage. Thisgeneticrearrangementtookplaceearlyafter divergence fromthegnathostomeofosteichthyan to thecartilaginouslineageandmayhaveoccurredafter http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0288 Thematic Review γ-MSH domain in teleost fish took place gradually The thirdorganizationalplanisfoundinray-finned α-MSH/ACTH, andβ-MSH/-endorphin); s

coevolutionary processesduringthePOMCevolution. coevolutionary teleost fishPOMCalsosuggestthepresenceofputative The lackofMC3Randthemainreceptorligandγ cores orlocalduplicationstogeneratePOMCandPNOC. POMC genetogenerateupfivedifferentMSHsequence POMC alsoincludesinternaltandemduplicationswithinthe PNOC, andPOMCprecursors.Thecomplexevolutionof genome duplicationrounds,generatingPENK,PDYN, million years ago. The family expanded thanks to the two emerged priortotheriseofjawlessvertebrates,over500 belonging totheopioid/orphaninfamily. Itprobably In summary, thePOMCisavertebratehormonalprecursor Summary process ofthepeptide/receptorsystem. γ-MSH inthePOMCprecursorsuggestsacoevolutionary in mammalian species. The absence of both MC3R and MC3R, whichhasbeenreportedastheγ-MSHreceptor the teleostpituitary. Interestingly, mostteleostfishlack the N-terminalregiondidnotaffectPOMCprocessingin and deletion evenaffectsthespacerregionbetweenγ-MSH fish. Inthislastlineage,γ-MSHdomainisabsentandthe inteleost fish, leadingtothecompletedeletionobserved gradual degenerationofPOMCprecursorsinray-finned to melanocortinreceptors.Allthesemutationssuggesta the coresequenceHFRW, whichiscrucialforbinding the sturgeonprecursoralsoexhibitsasubstitutionin POMC precursorsbutpresentingarsequences.Inaddition, Alrubaian J, Danielson P, Fitzpatrick M, Schreck C & Dores RM 1999 &Dores RM Danielson P, Schreck C Alrubaian J, Fitzpatrick M, References Chile GovernmentandMINECO,respectively. SN andLShad“FormaciondePersonalInvestiador(FPI)fellowshipsfrom Acknowledgment 52473R toJR. 46448-C3-3-R toJMC-R,AGL2013-46448-C3-1-RJLSandAGL2014- Grants fromMinisteriodeEconomíayCompetitividad(MINECO)AGL2013- Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest POMC evolution Published byBioscientifica Ltd. sturgeon Acipensertransmontanus. Peptides ofthe Cloning asecondproopiomelanocortin cDNAformpituitary α-MSH/ACTH. However, thismassivemodificationin Downloaded fromBioscientifica.com at10/01/202103:01:16AM 204 31–436. 56 : 4 -MSH in -MSH in T117 via freeaccess

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