Transcriptional and Epigenetic Regulation of POMC Gene Expression

56:4

j drouin POMC gene regulation 56:4 T99–T112 Thematic Review

60 YEARS OF POMC Transcriptional and epigenetic regulation of POMC gene expression

Correspondence should be addressed to Jacques Drouin J Drouin Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal, Email Québec, Canada [email protected]

Abstract Key Words Expression of the pro-opiomelanocortin (POMC) gene integrates numerous inputs ff gene regulation that reflect the developmental history of POMC-expressing cells of the pituitary and ff transcription hypothalamus, as well as their critical role in the endocrine system. These inputs are ff pituitary integrated at specific regulatory sequences within the promoter and pituitary or ff hypothalamus hypothalamic enhancers of the POMC locus. Investigations of developmental mechanisms ff ACTH and transcription factors (TFs) responsible for pituitary activation of POMC transcription ff MSH led to the discovery of the Pitx factors that have critical roles in pituitary development and striking patterning functions in embryonic development. Terminal differentiation of the two pituitary POMC lineages, the corticotrophs and melanotrophs, is controlled by Tpit; mutations of the human TPIT gene cause isolated adrenocorticotrophic hormone deficiency. Intermediate lobe and melanotroph identity is provided by the pioneer TF Pax7 that remodels chromatin to reveal a new repertoire of enhancers for Tpit action. Many signaling pathways regulate POMC transcription including activation by hypothalamic Journal of Molecular Endocrinology corticotrophin-releasing hormone acting through the orphan nuclear receptors of the Nur family and feedback repression by glucocorticoids and their glucocorticoid receptor. TFs of the basic helix-loop-helix, Smad, Stat, Etv, and nuclear factor-B families also mediate signals for control of POMC transcription. Whereas most of these regulatory processes are

conserved in different species, there are also notable differences between specific targets Journal of Molecular for regulation of the human compared with mouse POMC genes. Endocrinology (2016) 56, T99–T112

Introduction

The POMC gene has proven to be incredibly informative action of Pax7 on chromatin provides the selector function to study various aspects of gene regulation. Indeed, its that establishes the difference between intermediate and restricted expression in two pituitary cell lineages provided anterior pituitary derivatives. The first part of this review the system to identify cell-restricted transcription factors thus deals with mechanisms for developmental control of (TFs) such as Pitx1 and Tpit, and their interplay for setting POMC transcription in the two pituitary POMC lineages up cell-specific gene expression. Further, the quest to as well as with mechanisms for hypothalamic expression understand cell-specific regulation ofPOMC in these two of the single copy POMC gene. lineages, the corticotrophs of the anterior lobe (AL) and As central regulator of the hypothalamic–pituitary– the melanotrophs of the intermediate lobe (IL), led to the adrenal axis, POMC transcriptional regulatory mechanisms discovery of the pioneer TF role of Pax7. The pioneering integrate multiple inputs that ensure homeostasis of

http://jme.endocrinology-journals.org © 2016 Society for Endocrinology This paper is part of a thematic review section on 60 Years of POMC. DOI: 10.1530/JME-15-0289 Published by Bioscientifica Ltd. The Guest Editors for this section were Adrian Clark and Philip Lowry. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:03:15AM via free access

10.1530/JME-15-0289 Journal of Molecular Endocrinology transcription 1 (Pitx1, Ptx1) and for the Tbox TF Tpit (aka Tbx19). 1 (Pitx1,Ptx1)andforthe TboxTFTpit(akaTbx19). homeobox the bicoid-typehomeodomain TFpituitary ment thatisthebindingsite forcooperativebindingof ele- POMC expressionlieswithinacomposite regulatory et al (Therrien & and theiridentificationledtothecloningofcognate TFs two elementsthatconfercellspecificitytotheenhancer if not ubiquitous. However, detailed analyses identified binding sites for TFs that appear to be widely distributed, elements ( contain multipleregulatory −130 bpoftheratPOMCpromoterindicatedthatthey these enhancersequencesextendingbetween−480and corticotroph-specific enhancer. Moleculardissectionof sequences that behave as a critical upstream regulatory These wereshowntocontainaproximalpromoterand these 480 bp ofthe rat and human of sequences may also contribute to control regulatory regulation, notwithstanding the possibility that other site (TSS) contained most of the critical targets for that 480 bp upstream of the rat gene transcription start Hammer regulation intransgenicmice( large extenttheuniquefeaturesofPOMCtranscriptional importantly thattheyaresufficienttorecapitulatea culture experiments( that these sequencesexhibit cell-specific activity in cell The earlystudiesofPOMC5′-flankingsequencesindicated Mechanisms forpituitaryexpression ofthePOMCgene Developmental control of POMC transcription. currentknowledgeonthehormonalcontrolof surveys cell cycle control. Thus, the second part of this review pathogenesis ofthedisease,includingrelationshipswith on themechanismsofhormoneaction,butalso that causeCushing’s diseaseyieldednewinsight,notonly adenomas for Gc resistance in the corticotrophpituitary actions. Further, investigationofmechanismsaccounting particular, the interplay between activating and repressive insight intotheactionofnuclearreceptorsandin repression (Gc)ofthePOMCgenehaveprovidedunique this axis.StudiesofCRHactivationandglucocorticoid ( that alltheseelementsarejointlyrequiredforactivity Therrien &Drouin1991 DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org Thematic Review POMC transcription.Initialstudiesthusfocusedon . Thus, the corner stone for pituitary specificity of specificityof Thus, thecornerstonefor pituitary 2001 et al. 1990 ). Drouin 1993 ). Further, thetransgenicdataindicate Jeannotte , ). Many regulatory elementsare ). Manyregulatory Lamonerie j POMC

et al

POMC promoters.

. Printed inGreatBritain 1996 Fig. 1 t al.1988 et ) andmost , A), and Lamolet POMC ,

1 (NeuroD1)( helix-loop-helix (bHLH) factor neurogenic differentiation and itisatargetforheterodimerscontainingthebasic about 60bpupstreamofthePitx1andTpitbindingsites activity forcorticotrophexpression:thiselementislocated elementprovidescriticalcell-specific Another regulatory The rolesandpropertiesofthesefactorsarediscussednext. transcription ofthePOMCgene( ( elements,thePitx/TpitandNeuroD1bindingsites tory . 1996 et al subsets ofsignals( rat/mouse −7kbenhancersappeartoresponddifferent signal/hormone-dependent TFsandthehuman on theproximal−300bpenhancer( contains bindingsitesformanyofthesameTFsthatact species ( indifferent at about−7kbfromTSSthatisconserved the Cresiduecriticallyinteracts withlysine50ofthe binding specificityrecognizing themotif TAATC, where with theOtxsubfamilyand goosecoid,theyshareDNA similar DNAsequences( acids DNA-binding homeodomain and thus bind 60amino two aminoacidsintheirhighlyconserved The three members of this family differ only by one or two othermembersPitx2andPitx3( a subfamilyofthepaired/bicoidsubclass( novel homeodomain TF that defined theprototype of expression cloningacDNAforPitx1(Ptx1),then assay. Thissequencewasusedasprobe toobtainby to confer corticotroph-specific transcription in a reporter sequences identifiedoneelementforitsuniqueproperty Detailed analysesofupstreamPOMCpromoterregulatory and geneexpression Pitx1 andPitx2,TFsrequired forpituitarydevelopment mers ( is thepresenceofaTpitREpalbindingsiteforTpithomodi- featureofthe−7kbenhancer melanotrophs. Aconserved similar levelsoftranscriptioninbothcorticotrophsand preference for melanotrophs; together, theypromoted compared withthe−300bpenhancerthatshowedslight enhancer exhibitedslightlymoreactivityincorticotrophs seq analyses ( is revealedbychromatinimmunoprecipitation(ChIP)- sequences bycognateTFs occupancy of theseregulatory ( for orphannuclearreceptors(NR)oftheNursubfamily POMC generegulation Fig. 1 Philips Published byBioscientifica Ltd. The Fig. 1 A), synergistically control pituitary corticotroph corticotroph A), synergisticallycontrolpituitary

et al Langlais locus includes another enhancer situated POMC locus includes anotherenhancersituated ). ThePitxsubfamilywaslaterfoundtohave B). The enhancer is also under regulation by B). Theenhancerisalsounderregulationby . 1997 Fig. 2 Poulin

et al Langlais a ). In transgenic mice, the mouse −7 kb ). Thus,thesetwocell-specificregula-

et al . 2011 Downloaded fromBioscientifica.com at09/25/202110:03:15AM Tremblay . 1997 et al. 2011 ). Interestingly, thisenhancer ) as well as a binding site ) aswellabindingsite Poulin

et al ). Fig. 1 56 Gage

et al . : 2000 4 B); theinvivo

. et al 2000 ). Together Lamonerie . 1999 ). T100 a). via freeaccess

Journal of Molecular Endocrinology diagram representstranscriptionfactors showntobindtheenhancertogetherwithpredictedtranscriptionfactor bindingsites. predicted transcriptionfactorbindingsites(TFBS).(C)Themousehypothalamic enhancerisconstitutedoftwosubenhancersnamednPE1andnPE2.The these TFsarenotshownhereforclarity, buttheyarediscussedinthetext.(B) Themouse–7kbenhancerisrepresentedwithknownbindingTFstogether factors knowntobindtheenhancerandregulatePOMCtranscriptionarerepresentedbypictogramsonenhancer. Coactivatorsthatarerecruitedto well-conserved, exceptfora26bpinsertionintheratcomparedwithmouse sequences;positionsshownonthediagramarefortheratsequence.Transcription the mostusedtodissecttheseregulatorysequences,whereasinvivodata(i.e.ChIP-seq,Fig.2)areformouseenhancer. Thesesequencesare POMC. ThediagramsdepictcurrentknowledgeonDNAbindingtranscription factorsactingontheseenhancers.(A)Therat–300bpPOMCenhancerhasbeen Regulatory sequencesofthePOMCgene.Inadditiontopromoter, threeenhancersequencescontributetoeitherpituitaryorhypothalamic expressionof Figure 1 cell-specific transcription of the to this subfamily when we cloned Pitx1 for its role in et al.1989).Whileweareguiltyofgiving thenamePitx1 homeodomain thattypifies thesesubfamilies(Treisman http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0289 Thematic Review j POMC gene, it must be

Printed inGreatBritain is the master gene for specification of hindlimb identity its roleindevelopmentoforal ectodermderivatives,Pitx1 developmental rolesofPitx factors. Indeed,inadditionto recognized thatthisnamedoes notdojusticetothestriking POMC generegulation Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at09/25/202110:03:15AM 56 : 4 T101 via freeaccess Journal of Molecular Endocrinology except Ascl1datarecomputedfromZhanget al.(2015) on chromosome12,thePOMClocustogetherwithaplotofmammalianconservationforthislocus.ChIP-seqdataarefromauthor’s laboratory (RNApol II)isrevealedbyChIP-seq.ChIP-seqprofilesfortheindicatedfactorsareshownabovediagramsshowingmousechromosomalpositions(mm10) The mousePOMClocus.Invivooccupancyofthelocusbydifferent transcription factors,thecoactivatorp300andRNApolymeraseII Figure 2 of biology. thus providednewimpetustounforeseenareas pituitary 2003, t al. 2003, et preferentially degeneratein Parkinson’s disease (Hwang nigra, thesubsetofmidbraindopaminergicneuronsthat midbrain dopaminergic neurons of the ventral substantia et al.2007, partly redundantwithPitx2(Coulon Smidt eye and midbrain development (Semina ororalectoderm,butplays criticalrolesin in pituitary The thirdmemberofthesubfamilyPitx3isnotexpressed development(Charles with Pitx1inpituitary 1999, stomach (Gage development ofinternalorganssuchasheart,lungs,and Pitx2 isthemajoreffectorforleft–rightasymmetric (Lanctôt DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org Thematic Review Lu ). The discovery ofPitx1foritsroleinthe 2006). Thediscovery et al.1997)andinskeletalmyogenesiswhereitis et al. 1997, et al. 1999). Pitx2 has partly redundant roles ). Pitx3 is a critical survival genefor 2010, 2014).Pitx3isacriticalsurvival Nunes et al.1999b, et al. 2003, 1999b, Kitamura Szeto van den Munckhof j

et al. 1997, 1998, Printed inGreatBritain et al.2005). L’Honoré Lin et al. et al. Pitx1 interacts with the gonadotroph-restricted SF1 and et al.1998).Similartoitsrolein POMC transcription, gonadotrophins, prolactin,and growthhormone(Tremblay hormone-coding genessuchasthoseforthe pituitary Pitx1 playsasimilarcentral role fortranscriptionofother divergentspecies(Bumaschny across very It isnoteworthythatthePitx1bindingsiteconserved of theentire−300bpenhancerthatiscenteredaround. element, but also of the Tpit/Pitx composite regulatory 2001). Thus, Pitx1 not only constitutes the cornerstone are requiredfortranscriptionalactivity(Lamolet to cooperativelybindTpit;nevertheless,bothfactors absolute requirementforpriorbindingofPitx1inorder element(Tpit/PitxRE) createsan Pitx/Tpit regulatory of ahalf-siteforTpitbindingwithinthecomposite for anotherTF, Tpit,discussedbelow. Infact,thepresence elementthatcontainsaDNAbindingsequence regulatory essential foractivityanditispresentwithinacomposite POMC generegulation Published byBioscientifica Ltd. Within thePOMCpromoter, thePitx1bindingsiteis Downloaded fromBioscientifica.com at09/25/202110:03:15AM 56 : 4 et al.2007). T102 t al. et via freeaccess Journal of Molecular Endocrinology at thePOMClocus(Figs1B and2),thispalindromeis that containstwohalf-sites forrecognitionbyTpitand element(TpitREpal) identified apalindromeregulatory studies (Budry mode ofTpitactiongenome-wide asrevealedbyChIP-seq on Pitx1forbindingis,however, notthemostcommon enhancer. This composite element and the dependence combination requiredforactivityofthePOMC−300bp Together, thetwofactorsformacriticallyinter-dependent with Pitx1alreadyboundtoitssiteontheTpit/Pitx/RE. DNA sequence and its binding is highly cooperative its own,TpithasrelativelylowaffinityfortheTpit/PitxRE corticotrophs andmelanotrophs(Lamolet lineages,the highly restrictedexpressionintwopituitary led ustocloneTpit(alsoknownasTbx19),whichhas is similartotheconsensusbindingsiteforTboxfactors that the sequence motif flanking the Pitx1 binding site DNA binding sites of different DNA sequence. Recognition As discussedpreviously, theTpit/PitxREcontainstwo Tpit, aTboxTFrestricted toPOMClineages transcription programofeachlineage. lineagesiscriticalforthecell-specific adult pituitary development and their maintained expression in all Thus, Pitx1 and Pitx2 are essential for early pituitary development abortedattheearliestRathke’s pouchstage. redundancy betweenthesetwofactorsandpituitary However, the ( differentiation ofonlyonelineage, the ALcorticotrophs attheprimitiveRathke’sthe pituitary pouchstagewith 1999a (Lanctôt of Pitx1proteinintheadultpituitary lineages, thoselineagesthatexpressthehighestlevels underrepresentation ofthegonadotrophandPOMC gene inactivationhasthe least severephenotypewith ( glandderives oral ectodermfromwhichthepituitary earlyonsetofexpressioninthedeveloping their very expressionofPitx1andPitx2,with pan-pituitary lineage is consistent with thein eachpituitary (Tremblay et al.1998). transcription oftheprolactinandgrowthhormonegenes 1999), andwiththesomatolactotrope-restrictedPit1for transcription (Tremblay &Drouin1999, with thesignal-dependentfactorEgr1forcontrolofLHβ and their double knockouts (Charles phenotypesofknockoutmiceforPitx1,Pitx2, pituitary Gage Lanctôt http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0289 Thematic Review This roleascornerstoneforcell-specifictranscription ). . 1999b et al Pitx2 knockoutleadstoarresteddevelopmentof et al. 1997,1999a et al.2012).Indeed,genome-wideChIP-seq Pitx1, Pitx2 , Kitamura ). Thisisexemplifiedbythe . 1999, et al double knockout showed j

. 2005). et al Lin Printed inGreatBritain Tremblay et al. 2001).On ). . 1999). et al t al. et Pitx1 et al.

. 2001, et al the first Tpit-positive melanotrophs around e14.5 (Lamolet anterior lobearounddaye12ofmousedevelopmentand Tpit-positive corticotrophsaredetectedinthedeveloping Tpit isexpressedabout12hbeforePOMCandthefirst sites (Budry TF Etv1 that binds a sequence between Pitx and Tpit binding transcription isenhancedbyassociationwiththeEtsfamily otroph lineage: indeed, the a negativeregulatorfordifferentiationtowardthegonad- Unexpectedly, theTpitknockoutalsorevealedthatis differentiation oftheselineages(Pulichino melanotrophs: itisthusapositiveregulatorforterminal in micepreventsdifferentiationofcorticotrophsand not surprisingtofindthatinactivationoftheTpitgene adenomas (Vallette-Kasic humans, where it has proven useful to characterize pituitary POMClineagesincludingin marker ofthepituitary POMC transcription (Maira that alsocontributetoCRH-dependentactivationof mediated by transcriptional coactivators ofthe SRC family activation function.Thisfunctionisinpart Tpit/PitxRE isessentialandprovidestranscriptional (Langlais et al.2011). present and critical for activity of the −7 kb enhancer and this is a hallmark of neonatal, but not juvenile, IAD and thisisahallmarkofneonatal, butnotjuvenile,IAD and p27 by thecoexpressionoftwocellcycleinhibitors,p57 between progenitoranddifferentiatedstatusasrevealed plete thatcellfateswitchremaininsomewhatofalimbo troph-specific factorSF1.Further, cellsthatfailtocom- have switchedaremarkedbyexpressionofthegonado- intheALandcellsthat cell fateswitchisobserved of cellswithacellfatechangetogonadotroph.Asimilar ferentiate melanotrophs,butalsopresentswith10–15% gene mutations(Lamolet And indeed, we found that 2/3 IAD neonates have TPIT a conditionthathadonlybeen describedinafewchildren. adrenocorticotrophic hormone (ACTH)deficiency(IAD), that itsinactivationinhumanswouldproduceisolated role forPOMClineagedifferentiationledustopostulate The highlycell-restrictedexpressionofTpitanditscritical TPIT mutationsinisolatedACTHdeficiency (Bilodeau etal.2009). genitor state,andthelattermarkingdifferentiatedcells progenitors thatrecentlyexitedthecellcycleandpro - POMC generegulation Published byBioscientifica Ltd. In viewofthishighlycell-restrictedexpression,itwas Within thePOMCpromoter, Tpitbindingtothe Kip2 Pulichino , the former normally marking only pituitary , theformernormallymarkingonlypituitary et al. ). During pituitary development, development, 2011).Duringpituitary et al. et al. Downloaded fromBioscientifica.com at09/25/202110:03:15AM et al. 2001, 2003b Tpit et al. 2003). –/– ). Tpit is thus an excellent ). Tpitisthusanexcellent 2003a IL not only fails to dif- Pulichino 56 ). Tpit-dependent ). Tpit-dependent : 4 . 2003b). et al et al. 2003a T103 Kip1 via freeaccess )

Journal of Molecular Endocrinology development orinadults.In earlydevelopment,NeuroD1 melanotrophs donotexpress NeuroD1atanytimeduring lineages;incontrast,theIL with otheranteriorpituitary to specifythecorticotroph geneticprogramcompared the combinationofPitx1,Tpit, andNeuroD1mightsuffice (Batsche neighboring NurRE is coactivated by Rb, p107, or p130 whereas theactivityofNurfactorsthatbinds and therelatedcoactivatorp107(Batsche NeuroD1 heterodimersisenhancedbyrecruitmentofRb synergistic interaction.Transcriptional activationby NeuroD1 itselfinteractsdirectlywithTpittosupporttheir with thehomeodomainofPitx1(Poulin between theNeuroD1dimerizationpartner, suchasITF2, 1993). Thissynergismreliesondirectproteininteractions full activityofthe−300bpenhancer(Therrien& is criticalforsynergismwiththeTpit/PitxREand (discussed next).TheEbox for activation of element (NurRE)thatprovidessignal-dependentinputs and theotherpartconstitutedofNurresponse protein–protein interactions(Vallette-Kasic domain thatareincompatiblewithDNAbindingor replacement mutationswithintheDNAbindingTbox binding and/ortransactivation.ManyTPITmutationsare produce eithercompleteorseverelossoffunctionforDNA ( NeuroD1-containing bHLHheterodimers,theEbox bipartite with one part corresponding to a binding site for elementisalso (Therrien &Drouin1991).Thisregulatory transcription whenassociatedwiththeTpit/PitxRE elementthatsynergisticallyactivates a complexregulatory had identifiedinthedistalregionof−300bpenhancer POMCpromoter transcriptional studiesofthepituitary bHLH factorNeuroD1(Poulin specific expressionofPOMCalsoreliesontheneurogenic Pitx1 and POMC lineage identity by Tpit, corticotroph- specificityisconferred by Whereas broadpituitary Corticotroph specificity ofPOMCexpression useful forpatientfollow-up. Molecular diagnosisofTPIT corticoid replacementtherapy(Vallette-Kasic recognized, theconditioniseffectivelytreatedwithgluco- glycemia, convulsions,andrapiddeath;howeverwhen hypocortisolism leadstounstableglycemia,severehypo- or havechromosomaldeletions(Couture Other mutationscauseprematurestop,aberrantspicing, Vallette-Kasic DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org Thematic Review IAD isalethalconditioninchildrenastheresulting et al.2005a)asdiscussedlater. Itispossiblethat et al. POMC transcription in response to CRH 2005).IADcausing neuro mutations isthusextremely . 1997).Indeed,early et al (originallycalledDE2C) j

et al. mutations TPIT mutations Printed inGreatBritain et al.2005b), et al. . 2005). et al 2012). ). 2007). Drouin neuro , promoter (Fig.2),whereitbindstheEbox et al. ). 2015 It ispresent at both −7 kbenhancer and binding profile overlaps significantly with Tpit (Zhang Ascl1 contributestoPOMCtranscriptionanditsgenomic andJD,unpublishedobservations). et al.2015)(LBudry melanotrophs, corticotrophs,andgonadotrophs(Zhang in alladultlineageswithparticularlyhighlevels in the early Rathke’s pouch and remains expressed also inmelanotrophs.Indeed,Ascl1(Mash1)isexpressed contributes toPOMCexpressionincorticotrophsand over inadultcorticotrophs.Indeed,anotherbHLHfactor activity orwhetherotherneurogenicbHLHmighttake these low levelsof NeuroD1 are sufficient tomaintain this adult when NeuroD1 levelsarelow. Itisnotclear whether a role for the neurogenic bHLH target sequence in the (Lavoie both duringdevelopmentandintheadultpituitary resulted in severereduction of of theNeuroD1bindingsitewithinPOMCpromoter pituitaries (Lamolet inNeuroD1 knockout the transientphenotypeobserved of POMCexpressioninfetalcorticotrophsassupportedby might indicateatransientroleofNeuroD1inactivation the decreasingNeuroD1expressionincorticotrophs . 2004).TheexclusionofNeuroD1fromtheILand et al anterior lineages,inparticulargonadotrophs(Lamolet during adultlifewhenNeuroD1isalsoexpressedinother expression diminishesatmid-developmenttoremainlow is stronglyexpressed in developing corticotrophs, but its knockout does not prevent POMC POMC expression,Pax7knockoutdoesnotprevent and nootheroralectodermderivatives. pituitary . 2012).Indeed,Pax7isonlyexpressed intheILof et al of ILidentityandmelanotroph-specific transcription(Budry candidate, Pax7,whichturnsouttobeamajordeterminant mouse pituitaries.Thisapproachyieldedonestriking using developmentalexpressionprofilingofmicro-dissected transcription. Candidatesforthisspecificitywereidentified and hence,theydonotexplainmelanotroph-specificPOMC expression ofPOMCincorticotrophsandmelanotrophs lineage. Similarly, bothPitx1andTpitare ascriticalfor signaling pathwaysmodulatePOMCtranscriptionineach different promoter usagedoesnotexplainhowvery TSS incorticotrophsandmelanotrophsdifferential The singlecopyPOMCgeneistranscribedfromthesame Melanotroph identityand Pax7 Ebox Ascl1 maythusbethemajorbHLHfactoractingon POMC generegulation Published byBioscientifica Ltd. Whereas neuro et al.2008):theseinvivoanalysesclearlysupport inadultPOMCcells. gene inactivation results in abrogation of Tpit geneinactivationresultsinabrogation of t al.2004).However, mutagenesis et Downloaded fromBioscientifica.com at09/25/202110:03:15AM POMC promoter activity 56 : 4 neuro sequence. T104 POMC via freeaccess

Journal of Molecular Endocrinology the interpretationthatgeneticprogramofPax7 expression intheIL(althoughreduced),butPax7 the is expressedinallALcells,atasimilarlevel coid receptor(GR),whichisusuallynotexpressedinILbut V1b receptors are upregulated; in addition, the glucocorti- cotroph-specific markerssuchastheCRHandvasopressin melanotroph functionislost andtransferredtoskin. IL regressesduringmid-gestation andwherethepituitary of thistissueeveninspecies suchashumans,wherethe developmentandwiththemaintenanceproper pituitary with thedevelopmentalimportance ofthistissuefor development is consistentidentity during early pituitary to conditionlatercelldifferentiation.Selectionof IL the selectorgenemodelthatactsearlyindevelopment program ofgeneexpression.Suchroleisconsistentwith by Pax7 to implement the Tpit-dependent melanotroph and hencethisisconsistentwithepigenomeremodeling after Pax7-dependentchromatinremodeling(Fig.3B). acquires marksofactiveenhancers(H3K4me1,H3K27Ac) mark ofactivityinnormalcorticotrophAtT-20 cells,but specific enhancerofthePC2genethathasnoepigenetic such asTpit:agoodexampleofthisisthemelanotroph- upon Pax7binding,makingthemaccessibletootherTFs few thousandenhancerschangetheirchromatinstructure active enhancers(Budry the casebygenome-wideanalysesofchromatinmarksfor TFs suchasTpit(Fig.3A).Thiswasindeedshowntobe chromatin andchangesenhanceraccessibilitytoother to Tpit;hence,Pax7actsasapioneerTFthatremodels anotroph-specific targets(enhancers)becomeaccessible AtT-20 cells.However, followingPax7action,thesemel- target genesareinaccessibletoTpitinthecorticotroph action ofTFsbecausemanymelanotroph-specificTpit gene expressiongoesbeyondthesimplecombinatorial tion ofPax7forimplementationmelanotroph-specific Pax7 implementsthisidentityswitch:indeed,thecontribu- into thedifferentiatedstatus. progenitors outoftheprogenitorstateandengagethem suggested thatPax7mayhavetheabilitytodrivepituitary experiments corroboratedthisinterpretationandfurther determination ofILidentity. Gain-of-functiontransgenic corticotroph programsupportingamajorroleofPax7in cells issignificantly(butnotcompletely)switchedtothe tors are severely reduced in the as theproteinconvertasePC2anddopamineDRD2recep- troph to corticotroph. Indeed, melanotroph markers such shows astrikingswitchinexpressionprofilefrommelano- http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0289 Thematic Review Pax7 Pax7 expressionappearsslightlybeforeTpitintheIL Most striking,however, isthemechanismbywhich –/– IL. Global analysis of gene expression supports IL.Globalanalysisofgeneexpressionsupports . 2012).Itwasfoundthata et al Pax7 j

IL, whereas corti- Printed inGreatBritain –/– –/– IL IL IL IL enhancer (Langlaiset al.2011). are completelyabsentfromthehypothalamic−12kb 2),but enhancer(Figs 1Cand and the−7kbpituitary cellsarerestrictedtothe5′-proximalsequences in pituitary chromatin marksassociatedwithtranscriptionalactivity andhypothalamicexpression, sequences forpituitary blocks Stat3bydirectinteraction(Yang ( leptin; thisactionismediatedbytheJak2/Stat3pathway 2011). HypothalamicPOMCexpressionisstimulatedby element isalsoatargetofestrogenreceptor(de Souza the hypothalamicenhancer(Nasif target sequenceswithinthenPE1andnPE2subdomainsof for hypothalamicexpressionofPOMC;further, Isl1actson studies indicated that the TF Isl1is a majordeterminant subregions, nPEIandnPE2(deSouza −12 kbenhancer(Fig.1C)wassubdividedintotwo activity(Rubinstein pituitary 2015). Conversely, the−12kbenhancerdoesnothaveany hypothalamic expression(Young −12 kbfromthePOMCTSSisprimarilyresponsiblefor a transgenicassay, whereasanenhancerpresentatabout the sequences. Indeed,the5′ regulatory expression ofPOMCcomparedwiththepituitary have clearlyidentifiedseparatesequencesforhypothalamic sequences & Bouret2013).AnalysesofPOMCregulatory hypothalamic POMCnetwork(Padilla neurons containstheprogenitorsofafractionadult Elkabes neurons in the developing diencephalon (Gee is strongPOMCexpressioninaclusterofventrallylocated Ramamoorthy plays akeyroleinenergyhomeostasis(Mountjoy2010, of thehypothalamus;inparticular, thePOMCergicsystem The Hypothalamic expression ofPOMC 1985, signaling activates and fromthemodelcells AtT-20. Inparallel,CRH corticotrophs of POMC-derivedpeptides from pituitary The hypothalamichormone CRHstimulatestherelease signaling Activation ofpituitarytranscriptionfunctionbyCRH Hormonal control ofPOMCtranscription POMC generegulation Bates Published byBioscientifica Ltd. In agreement with the clear separation of regulatory In agreementwiththeclearseparationofregulatory TSS do not drive hypothalamic expression in POMC TSSdonotdrivehypothalamicexpressionin gene is expressed in a few thousand neurons POMC geneisexpressedinafewthousandneurons et al. 1987) andmayactthroughdifferent signaling et al. ), and is counteracted by the FoxO1 TF that 2003),andiscounteractedbytheFoxO1TFthat ). This early cluster of POMC-positive 1989).ThisearlyclusterofPOMC-positive et al. POMC transcription (Gagner & Drouin ). During fetal development, there 2015).Duringfetaldevelopment,there Downloaded fromBioscientifica.com at09/25/202110:03:15AM proximal −480 bp upstream of proximal−480bpupstreamof et al. ). The hypothalamic 1993).Thehypothalamic et al. et al. et al. 56 et al. et al. 1998, ). The nPE2 2015).ThenPE2 ), and recent 2005),andrecent : 4 2009). 2010, et al. Lam T105 Coupe Coupe 1983, et al. et al. Gali Gali via freeaccess Journal of Molecular Endocrinology pathway (Kovalovsky activation ofthecAMP/PKA pathwayandoftheMAPK pathways. Indeed,CRHaction onitsreceptorleadsto PC2 enhancerbeforeandafterPax7. allow Tpitbindingandenhanceractivity. ChIP-seqprofilesillustratethechanges intranscriptionfactoroccupancyandchromatinstateatthe–146kb representation ofchromatinremodelingexertedbyPax7atmelanotroph-specific enhancers.(B)ThePC2gene–146kbenhancerisremodeledbyPax7to Pioneer factoractionofPax7opensnewenhancerrepertoireforimplementation ofthemelanotrophgeneexpressionprogram.(A) Schematic Figure 3 DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org Thematic Review et al. 2002, j

. 2003 a), the et al Printed inGreatBritain than antagonizingeachother. CRHsignalinghasbeen where thesetwopathways arepositivelylinkedrather corticotrophs beingoneoftheunusualtissues pituitary POMC generegulation Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at09/25/202110:03:15AM 56 : 4 T106 via freeaccess Journal of Molecular Endocrinology constitutively activeandthe otherbeingdependenton domain was dissected into two subdomains, one being NGFI-B N-terminal AF1 domain. For NGFI-B, the AF1 is dependentonMAPK signals andactivatesthe Nur factors is through the N-terminus. The recruitment C-terminal AF2 activation domain, their recruitment to coactivators arerecruitedtotheligand-dependent contrast tomanyligand-dependentNRswhereSRC vation oftheMAPKpathway(Maira for NGFI-Bactivation,inparticularresponsetoacti- mer targetofaction,theNBRE,isafarlesspotent that issimilartoonehalf-siteoftheNurRE.Thismono- NRs actedprimarilyasmonomersonatargetsequence comparison tothepreviouslyheldviewthattheseorphan nism ofactionfortheNursubfamilyorphanNRsby Indeed, thePOMCgeneNurREdefinedthisdimermecha- vated throughtheMAPKpathway(Philips growthfactorI-B(NGFI-B) (Nur77) thatareacti- nerve palindromic target of action for orphan NR related to element defined a in the ratpromoter:thisregulatory elementlocatedat−404bp mapped toatargetregulatory POMC transcriptionbyCRHremainsilldefined. activates theseTFsandtheirroleinhormonalcontrolof et al. 1991, of AP1wereidentifiedonthePOMCpromoter(Boutillier heterodimers betweenjun associated withactivationofAP1TFsconstituted on Nurdimersthanmonomers(Maira group isfargreater(byalmosttwoordersofmagnitude) including theNurfactors,buttheiractiononthislatter Indeed, thesecoactivatorsinteractwithmanyNRs of the SRC family, including SRC1, SRC2, and SRC3. the NurandNeuroD1dimersisenhancedbycoactivators Transcriptional activation of thePOMCgenethrough Coactivators ofCRHsignaling POMC transcription. of MAPK8decreasesErk1/2andNurfactoractivity, hence of theMAPK8mRNA(Zhang regulated byamiRNA,miR-375,whichtargetsthe3′ and NOR1(Campos-Melo NGFI-B (Nur77),thefactorsNur-relatedfactor1(Nurr1) The NursubfamilyoforphanNRsincludesinadditionto three membersofthisNRsubfamily(Maira of aconsensusNurREthatisequallyactivatedbythe dimers thatincludeNGFI-Bcomparedwiththeactivity POMC gene NurREexhibitsa preference for Nur factor http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0289 Thematic Review A majortargetofCRHactiononPOMCtranscriptionwas are negatively CRH andNurfactoractivationofPOMCarenegatively 1995). Growth and serum stimulation also et al. and fosputativetargets et al. 2013). j

et al. . 2003b et al Printed inGreatBritain 2003b . 1997a et al et al. ). 1999). ). The -UTR -UTR ). In ). ).

by MAPK. followingactivationa siteofintensephosphorylation MAPK signaling(Maira promoter (Drouin element (nGRE)centeredat−63bpoftheratPOMC to identificationofanegativeglucocorticoidresponse et al. 1988).Furtherdissectionofthesesequencesledfirst to bothCRHactivationandGcrepression(Tremblay POMC geneindicatedthatthesesequencesweresensitive transgenic analysis of the5′ and theirreceptor, GR(Gagner&Drouin1985).Thefirst the In counterbalancetoCRHactivation,transcriptionof Glucocorticoid repression ofPOMCtranscription et al. 2005a through directprotein–proteininteractions(Batsche enhanced byRbanditsrelatedproteinsp107p130 with thatofSRC2.NurfactoractionontheNurREisalso coactivator activityandthiscoactivationissynergistic ing andNurRE-dependenttranscription,Tif1 β et al. which wasprimarilyknownasacorepressor(Rambaud included thecoregulator Tif1β CRH-dependent proteinsrecruitedtoNGFI-Bcomplexes ing identified another unexpectedcoactivator. Indeed, proteins associatedwithNGFI-BfollowingCRHsignal- sequences totheNurRE(Philips AtT-20 cellswithluciferasereportersmapped responsive responsive sequences using transient transfection in relative toanothermechanism.Indeed,mappingofGc is stillunclearwhichinvivocontextwouldfavorthis responsible forGcrepressioninothercontextsandit repression in some contexts, they may notbe primarily sequencesconferGc 1993). WhilethenGREregulatory homodimer followedbymonomerbinding(Drouin this nGRE is tobind three moieties of GR in the form of a ( repress transcription by a transrepression mechanism through protein–proteininteractionsandthusmay sequences directly, but that it interacts with Nur factors investigation indicatedthatGRdoesnotbindthese present at the dependent onBRG1.BRG1 appearstobeconstitutively the histonedeacetylase2 (HDAC2)andthisisalso et al. the SWI/SNFchromatinremodeling complex(Bilodeau recruitment requiresBRG1,theATPase componentof POMC generegulation Philips Published byBioscientifica Ltd. Direct identification by mass spectrometry ofDirect identificationbymassspectrometry POMC geneissubjecttofeedbackrepressionbyGc 2006).TheGRtransrepressioncomplex alsorecruits 2009).However, inthecontextofCRHsignal- t al.1997b et ). POMC promoter before Gc/GR activation. et al. , Martens et al. 2003b 1989).Theuniquepropertyof Downloaded fromBioscientifica.com at09/25/202110:03:15AM regulatory sequencesofthe regulatory (also known as KAP1), et al. . 1997a et al ). ThisAF1domainis 56 2005).ThisGR : 4 , b ). Further exhibits T107 et al. via freeaccess

Journal of Molecular Endocrinology adenomas alsooftenexhibit thelossofp27 corticotroph adenomas(Jordan thatcyclinEisoverexpressed inabout75%of observed ( in over50%ofadenomas,bothdogsandhumans proteins, BRG1orHDAC2,mayaccountforGcresistance adenomas. Thelossofnuclearexpressioneitherthese essential componentsforGcfeedbackinCushing’s disease of POMCledtoassessmenttheexpressionthesetwo of criticalrolesBRG1andHDAC2forGRtransrepression response mechanismsthatarealtered.Theidentification 2015). Rather, itisoftentheGc-dependentcorticotroph that overexpressthechaperoneHSP90(Riebold but processing of GR may be altered in a subset of adenomas rarely ascribed to GR mutations (Lamberts 2002), was very corticotroph adenomasofpatientswithCushing’s disease disease (Liddle1960).ThecauseofGcresistancein used as a discriminating clinical test to diagnose Cushing’s POMCtoGcisindeed relative insensitivityofpituitary POMC(Drouin repression onpituitary Cushing’s diseaseischaracterizedbythelossofGcfeedback Glucocorticoid repression ofPOMCandCushing’s disease comparing different genomes. ishighwhen that theoverallsequenceconservation of importance ofthe−7kbenhancerforhormonalcontrol Gc/GR repression(Langlais enhancer appearedmoresensitivetoCRHactivationand activation andGcrepression,thehuman−7kb enhancer) appearprimarilyresponsibleforbothCRH 5 ( of transcriptionmayhavespecies-specificfeatures that theirrelativeimportanceforhormonalcontrol −7 kbenhancerand5′ transrepression, butcomparisonofhumanandmouse supported aroleforGR-dependentrepressionthrough hormone-regulated −7 kb POMCgeneenhancerfurther at thePOMCpromoterandgenebody. ofthe Discovery GR recruitmentresultsindecreasedhistoneacetylation p27 the lossofBRG1intheseadenomastogetherwith of Accordingly, upregulationofcyclinEiscorrelated with nomas mayalsoleadtoupregulationofcyclin E. tributions ofcyclinEoverexpression andlossofp27 (Lidhar Bilodeau Langlais ′ DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org proximal regulatory sequences(ratherthan−7kb proximalregulatory Thematic Review POMC maydifferbetweenspeciesdespitethefact Kip1 The lossofBRG1expressionincorticotrophade- (Roussel-Gervais . 1999).Directassessmentoftherelative con- et al et al. 2006). t al. 2011). Indeed, whereas the rodent et regulatory sequencessuggested regulatory et al.2010).Ithadalreadybeen et al. 2011).Thus,therelative et al.2000)andthatthese j

et al. Printed inGreatBritain Kip1 ). The 2007). The expression et al. Kip1

ACTH deficiencyisascribed toactivatingmutationsin However, itisnoteworthythataform ofhuman et al. (NFKB) alsostimulatesPOMC transcription(Takayasu loop onthesystem. and Smad7mayalsooperateasanautocrineregulatory from studiesinAtT-20 Smad6 cellsthattheinhibitory exogenous ligandsrepressPOMCtranscription,itappears recruitment totheTpit/PitxRE(Nudi general partnerSmad4actonthePOMCpromoterthrough containing asignalresponsiveSmadtogetherwiththe family ofTFs.TheSmadfactorsactingasheterodimers POMC transcriptionthroughtheiractionontheSmad Signals related totransforming growth factor-βmodulate expression Other signalingpathwaysaffecting POMCgene resistance toGcfeedback. to thehallmarkofcorticotroph adenomas, namelytheir targets ofUSP8maybeinvolvedinlinkingthesemutations account for Gc resistance and hence, it is likely that other ACTH secretion.Howeverinitself,thisactiondoesnot al.2015)andthismaycontributetoupregulationof et signaling likely increases caused bytheUSP8mutations.TheupregulationofEGFR receptor due to enhanced deubiquitination activity EGF signaling was ascribed to increased cell surface EGF mutations havepersistentEGFsignaling.Thesustained analyses indicatethatcorticotrophadenomaswithUSP8 have manydifferentsubstrates(Ge et al.2015, the analysis. Indeed,thisrevealedrecurrentmutationsin Cushing’s diseasewasprovidedthroughtranscriptome A newandsignificantinroadintothepathogenesisof Defective signalinginCushing’s disease etal.2016). (Roussel-Gervais of Gc-dependentcellcycleregulatorsinAtT-20 cells cycle progressionwasidentifiedinagenome-widescreen adenomas. Indeed,theCables1negativeregulatorofcell found tobeGc-dependentandlostin~55%ofCushing’s Gervais et al.2010). Gervais bigger, faster, andmoreaggressiveadenomas(Roussel- showed asynergisticeffectinmousemodelleadingto POMC generegulation Published byBioscientifica Ltd. USP8 gene that encodes a deubiquitinase (Perez-Rivas The inflammatory responseTFnuclear factor-BThe inflammatory Another regulatorofp27 2010),butdetailsofthisaction remainlimited. Reincke et al.2015).AlthoughUSP8could Downloaded fromBioscientifica.com at09/25/202110:03:15AM POMC gene expression (Reincke Kip1 , Cables1,wasrecently et al.2015),current 56 et al.2005).While : 4 T108 via freeaccess

Journal of Molecular Endocrinology ( immunodeficiency constitutestheDavidsyndrome immunodeficiency andtheassociationofIADwith 2014 the relatedNFKB2gene( species suchashumanandmouse. may haveevolveddifferently, evenforrelativelyclose butthatthespecifictargets processes arewellconserved, other similarcomparisons, revealsthattheregulatory of the knowledge to the human noteworthy thattheemergingpicturefortransposition interplays. However,understand their regulatory it is pathways andtheyprovidetheconceptualbackdrop to crosstalk betweenvariousdevelopmentalandsignaling informativeofthe mechanismsand studies havebeenvery mostly performedinmousemodels,cells,andvivo.These three decadesonPOMCgeneregulationfromstudies This reviewhasoutlinedknowledgegainedoverthelast Conclusion CRH ( ACTH releaseandthisactionmaybesynergisticwith and interleukin(IL)-6stimulatePOMCtranscription factor(LIF) Cytokines relatedtoleukemiainhibitory The cytokineandSTAT signalingonPOMCtranscription hormonal regulation. of rate-limiting processes,suchastherelativeimportance havedifferencesin appear to again, humanand mouse development andinalllikelihood,function.Once of have been well documented in human patients, the loss (Akita there, itmayprovideparacrineandautocrineregulation glandand In addition,LIFisproducedwithinthepituitary responses. connection forcoordinationofinflammatory this mayprovidean important immune-endocrine function;hence, responsewithpituitary inflammatory tocoordinate to inflammationandthusmayserve from thehypothalamusandsystemicallyinresponse et al this effectisexertedthroughtransrepression( of ( promoter, oneat−380bpandtheother−150 of theStat3TF, whichhastwobindingsitesonthePOMC Fig. 2 Quentien http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0289 Thematic Review POMC transcriptionisantagonizedbyGcandGR, Nfkb2 functioninmousedoesnotaffectpituitary NFKB2 ortheroleof−7kbPOMCenhancerfor . 2012 ). TheseNFKB2mutationsalsocausevariable ). AsforCRH-dependentactivation,LIFactivation et al Ray

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1995).Thesecytokinesactthroughactivation et al et al . . 1996 2012 ). BothIL-6andLIFarereleased ). While these NFK2B Chen

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Printed inGreatBritain , Brue mutations Langlais

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Brue T, Quentien M, Khetchoumian K, Bensa M, Capo-Chichi J, Capo-Chichi J, Bensa M, Khetchoumian K, Brue T, Quentien M, & Roberts JL Lundblad JR, Lorang D, Monnier D, Boutillier AL, 1991Theprotooncogene &Loeffler JP Sassone-Corsi P Boutillier AL, 2009 Distinctdevelopmental &Drouin J Roussel-Gervais A Bilodeau S, Brue T, Gauthier Y, Vallette-Kasic S, Figarella-Branger D, Bilodeau S, 2005b &Drouin J Moschopoulos P, Bilodeau S Batsche E, Desroches J, 2005a &Drouin J Gauthier Y Bilodeau S, Desroches J, Batsche E, Tso AW, Schubert M, Dundon TA, Stearns WH, Bates SH, Wang Y, Akita S,Webster J,RenSG,Takino H,SaidJ,ZandO&MelmedS References laboratory overtheyearswererealartisansofcontributions. students, postdocs,andscientistswhohaveworkedintheauthor’s preparation, and to T Abdul-Rasul for secretarial assistance. The talented The authoristhankfultoABalsalobreandMayranforhelpwithfigure Acknowledgements Institute ofCanada. the CanadianInstitutesofHealthResearchandbyNationalCancer Research performedintheauthor’s laboratoryhasbeenfundedby Funding perceived asprejudicingtheimpartialityofthisreview. The authordeclaresthatthereisnoconflictofinterestcouldbe Declaration ofinterest POMC generegulation Published byBioscientifica Ltd. M413427200) 280 19746–19756. ofBiologicalChemistry receptors andhormoneresponsiveness.Journal Rb enhancesp160/SRCcoactivator-dependentactivityofnuclear nature01388) patients withDAVID syndrome,havingvariableendocrineand 2014 MutationsinNFKB2andpotential geneticheterogeneityin . et al Papadimitriou DT, Pagnier A, Nassif C, Balsalobre A, Delemer B, Molecular Endocrinology -independent pathways:characterizationofanAP1siteinexon1. proopiomelanocortin transcriptionbycFos-dependentand 1995Corticotropin-releasinghormonestimulates Loeffler JP Endocrinology cels. Molecular proopiomelanocortin genetranscriptioninpituitary c-fos isinducedbycorticotropin-releasingfactorandstimulates (doi:10.1128/MCB.01885-08) differentiated cells.MolecularandCellularBiology of progenitorcellcycleexitfromre-entry pituitary roles ofcellcycleinhibitorsp57Kip2andp27Kip1distinguish 2871–2886. gene andmisexpressioninCushingdisease.Genes&Development POMC Role ofBrg1andHDAC2inGRtrans-repressionpituitary . 2006 et al Hanson J, Stratakis S, Batista D, Berthelet F, Lacroix A, Biological Chemistry of coactivators ofNeuroD1toenhancegenetranscription.Journal Retinoblastoma andtherelatedpocketproteinp107actas but notreproduction.Nature STAT3 signalling isrequiredforleptinregulationofenergybalance . 2003 et al Maratos-Flier E, Haq AK, Lavery HJ, Banks AS, Clinical Investigation ofadrenocorticotropin hormonesynthesisandsecretion.Journal factor.inhibitory regulationof Novelintrapituitary expressionofleukemia1995 Humanandmurinepituitary (doi:10.1101/gad.1444606) 5 1301–1310. (doi:10.1074/jbc.M413428200) 280 16088–16095. 95 1288–1298. 9 745–755. Downloaded fromBioscientifica.com at09/25/202110:03:15AM (doi:10.1210/mend-5-9-1301) 421 856–859. (doi:10.1210/mend.9.6.8592520) (doi:10.1172/JCI117779) (doi:10.1074/jbc. 56 (doi:10.1038/ : 4 29 1895–1908. T109

20 via freeaccess Journal of Molecular Endocrinology Drouin J, Bilodeau S & Vallette-Kasic S 2007Of old andnewdiseases: &Vallette-Kasic S Bilodeau S Drouin J, & Nemer M Gauthier Y, DeLéan A, Chamberland M, Sun YL, Drouin J, & 1989 Eriksson P Wrange Ö Nemer M, Trifiro MA, Plante RK, Drouin J, 2011 &Rubinsten M Low MJ Levi DH, Lopez-Leal R, Nasif S, de Souza FS, Bumaschny V, Low MJ Santangelo AM, Smart JL, Avale ME, de Souza FS, Houang Y, Wherett D, Baechler A, Barlier A, Saveanu A, Couture C, 2013Developmentofthehypothalamic &Bouret SG Coupe B Coulon V, L’Honoré A, vanden Ouimette JF, Dumontier É, Franks ZF, Durtschi JD, Kumanovics A, Coonrod EM, Chen K, 2005PITXgenes &Gage PJ Camper SA Drouin J, Suh H, Charles MA, &Andres ME Gysling K Sanchez N, Galleguillos D, Campos-Melo D, Santangelo AM, LopezLeal RA, Bumaschny VF, deSouza FS, L’Honore A, Gauthier Y, Khetchoumian K, Balsalobre A, Budry L, 2011TheEtsfactorEtv1 &Drouin J Balsalobre A Couture C, Budry L, Elkabes S, Loh YP, &Wray S 1989Prenatalontogenesisof Elkabes S, Nieburgs A DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org Thematic Review Genetics ACTHexcess(Cushing)anddeficiency.genetics ofpituitary Clinical 145–156. element ofthehormone-repressedPOMCgene.EMBOJournal 1993NovelglucocorticoidreceptorcomplexwithDNA Schmidt TJ (doi:10.1128/MCB.9.12.5305) gene transcription.MolecularandCellularBiology required forhormone-dependentrepressionofpro-opiomelanocortin Glucocorticoid receptorbindingtoaspecificDNAsequenceis 181–187. ofPharmacology neuron-specific enhancernPE2.European Journal motifpresent inthe hypothalamic neuronsandbindstoaconserved The estrogenreceptoralphacolocalizeswithproopiomelanocortinin 3076–3086. phylogenetic footprinting.MolecularandCellularBiology proopiomelanocortin genebytransgenicmouseanalysisand 2005Identificationofneuronalenhancersthe & Rubinstein M jc.2011-1659) of ClinicalEndocrinology&Metabolism isolated ACTHdeficiencypatientswithTPITgenemutations.Journal homogeneity andgenotypicvariabilityinalargeseriesofcongenital . 2012Phenotypic et al Fluck C, Maes D, Lebouc Y, Fassnacht M, (doi:10.3389/fendo.2013.00038) melanocortin system.Frontiers inEndocrinology(Lausanne) Chemistry ofBiological Pitx3 geneexpressioninearlymusclecells.Journal 2007Amuscle-specificpromoterdirects Drouin J Munckhof P & (doi:10.1016/j.ajhg.2013.09.009) immunodeficiency. NF-kappaB pathwayinthepathogenesisofcommonvariable Germline mutationsinNFKB2implicatethenoncanonical . 2013 et al Ridge PG, Wu W, Augustine NH, Margraf RL, Heikal NM, Endocrinology andLhx3activation.Molecular are requiredforcellsurvival Molecular Neuroscience 2013 Nurtranscriptionfactorsinstressandaddiction.Frontiers in 21 2738–2749.(doi:10.1210/me.2006-0557) despite greatpromotersequencedivergence.MolecularEndocrinology atthevertebrateextremes POMCisconserved regulation ofpituitary 2007Transcriptional &Rubinstein M Low MJ Levi DH, Baetscher M, 2299–2310. pioneer actiononchromatinremodeling.Genes&Development cellfatesthroughits selector genePax7dictatesalternatepituitary 2012The &Drouin J Meij B Brue T,Vallette S, Figarella-Branger D, 25387–25396. ofBiologicalChemistry (POMC) genetranscription.Journal pro-opiomelanocortin interacts withTpitproteinforpituitary s12881-014-0139-9) immune deficiencies.BMCMedicalGenetics pituitary gland:anin situhybridizationandimmunocytochemical pituitary systemand pro-opiomelanocortin inthemouse centralnervous 72 175–182.(doi:10.1111/j.1399-0004.2007.00877.x) (doi:10.1016/j.ejphar.2010.10.114) 282 33192–33200.(doi:10.1074/jbc.M706119200) (doi:10.1128/MCB.25.8.3076-3086.2005) (doi:10.1101/gad.200436.112) 19 1893–1903.(doi:10.1210/me.2005-0052) (doi:10.1074/jbc.M110.202788) American Journal ofHumanGenetics American Journal 6 44.(doi:10.3389/fnmol.2013.00044) 97 486–495.(doi:10.1210/ j

9 5305–5314. Printed inGreatBritain 93 812–824. 25 286 4 38.

12 26 660 L’Honoré A, Coulon V, Marcil A, Lebel M, Lafrance-Vanasse J, Gage PJ, L’Honoré A, Gage PJ, Lafrance-Vanasse J, Coulon V, Lebel M, Marcil A, Pereda MP, Hochbaum D, Liberman AC, Refojo D, Kovalovsky D, L’Honore A, Commere PH, Ouimette JF, Montarras D, Drouin J & Drouin J Ouimette JF,L’Honore A, Montarras D, Commere PH, 2010Pitx2 L’Honoré A, &Drouin J Ouimette JF, LavertuJolin M Gage PJ, Suh HY & Camper SA 1999bDosagerequirementofPitx2for &Camper SA Suh HY Gage PJ, 1999aThebicoid-relatedPitxgenefamily &Camper SA Suh H Gage PJ, Kitamura K, Miura H, Miyagawa-Tomita S, Yanazawa M, Katoh-Fukui Y, Miura H, Kitamura K, 2000Cyclin &Grossman AB Lowe DG Korbonits M, Lidhar K, Jordan S, 1987 &Drouin J Chamberland M Trifiro MA, Plante RK, Jeannotte L, 2003Selective Hwang DY, &Kim KS Ardayfio P, Semina EV Kang UJ, and 1990Pituitary-specific &Low MJ Fairchild-Huntress V Hammer GD, &Watson SJ 1983 Thompson R Roberts JL, Chen CLC, Gee CE, 2015 &Du C Pandita TK Li K, Lu J, Pandita RK, Ren J, Che L, Ge C, 2015 &White A Harno E Gali Ramamoorthy T, Begum G, 1987Tissue-specific regulationofpituitary &Drouin J Gagner J-P 1985Oppositeregulationofpro- &Drouin J Gagner J-P POMC generegulation Published byBioscientifica Ltd. Biology of 2007Sequentialexpressionandredundancy &Drouin J Camper SA Molecular Endocrinology involvement ofcalcium,proteinkinaseA,andMAPKpathways. induction ofNUR77/NURR1incorticotrophsbyCRH/cAMP: 2002Activation and &Arzt E Holsboer F Stalla GK, Coso OA, devcel.2014.04.006) for fetalmyogenesis.DevelopmentalCell 2014Redoxregulation byPitx2andPitx3iscritical Buckingham M dev.053421) somitic myogenesis.Development defines alternatepathwaysactingthroughMyoDduringlimband development ofmultipleorgans.Development s003359900970) in development.MammalianGenome 3806(89)90145-4) study. isomerism. heart, extra-andperiocularmesodermrightpulmonary Mouse Pitx2deficiencyleadstoanomaliesoftheventralbodywall, Motegi Y,. 1999 Nakahara Y, Suehiro A, et al Ohuchi H, Suzuki R, eje.0.143R001) ofEndocrinology European Journal D andcyclinEexpressioninnormaladenomatouspituitary. MCB.7.11.4058) Molecular andCellularBiology Tissue-specific activityofthepro-opioomelanocortingenepromoter. (doi:10.1016/S0169-328X(03)00162-1) deficient aphakiamice.MolecularBrainResearch loss ofdopaminergicneuronsinthesubstantianigraPitx3- Endocrinology proopiomelanocortin promoterintransgenicmice.Molecular hormonally regulatedgeneexpressiondirectedbytherat 374–376. hypothalamus byinsitucDNA-mRNAhybridization.Nature Identification ofpro-opiomelanocortinneuronesinrat (doi:10.1073/pnas.1418335112) USP8 deubiquitinationofBRIT1.PNAS BRUCE regulatesDNAdouble-strandbreakresponsebypromoting (doi:10.3389/fnins.2015.00126) impact onenergybalancecontrol.Frontiers inNeuroscience Developmental programmingofhypothalamicneuronalcircuits: mend-1-10-677) glucocorticoids. hormone, 3’,5’-cyclicadenosinemonophosphate,and proopiomelanocortin genetranscriptionbycorticotropin-releasing 7207(85)90154-6) Molecular andCellularEndocrinology opiomelanocortin genetranscriptionbyglucocorticoidsandCRH. Pitx2 andPitx3genesduringmuscledevelopment.Developmental Developmental BrainResearch 307 421–433.(doi:10.1016/j.ydbio.2007.04.034) (doi:10.1038/306374a0) Development 4 1689–1697.(doi:10.1210/mend-4-11-1689) Molecular Endocrinology 16 1638–1651.(doi:10.1210/mend.16.7.0863) 126 5749–5758. Downloaded fromBioscientifica.com at09/25/202110:03:15AM 7 4058–4064.(doi:10.1128/ 143 R1–R6.(doi:10.1530/ 137 3847–3856.(doi:10.1242/ 46 85–95.(doi:10.1016/0165- 40 25–32.(doi:10.1016/0303- 10 197–200.(doi:10.1007/ 112 E1210–E1219. 1 677–682.(doi:10.1210/ 29 392–405.(doi:10.1016/j. 56 126 4643–4651. : 114 123–131. 4 9 126. 306 T110 via freeaccess Journal of Molecular Endocrinology Maira MH, Couture C, Le Martelot G, Pulichino AM, Bilodeau S & Bilodeau S LeMartelot G,Pulichino AM, Couture C, Maira MH, 1999Heterodimerization &Drouin J Philips A Martens C, Maira MH, Lu MF, Pressman C, Dyer R, Johnson RL & Martin JF 1999Functionof &Martin JF Johnson RL Dyer R, Lu MF, Pressman C, Izpisua Briata P, Liu R, O’Connell S, Szeto D, Kioussi C, Lin CR, Lu X, Kaltsas G, Khalimova Z, Jordan S, Korbonits M, Lidhar K, 1960TestsLiddle GW suppressibilityinthe ofpituitary-adrenal 2008Developmental &Drouin J Balsalobre A Budry L, Lavoie PL, 2012TheStat3/GRinteractioncode: &Drouin J Couture C Langlais D, 2011Apituitary- &Drouin J Sylvain-Drolet G Couture C, Langlais D, Lanctôt C, Moreau A, Chamberland M, Tremblay ML & Drouin J 1999b Tremblay ML &Drouin J Chamberland M, Moreau A, Lanctôt C, homeobox1(Ptx1)is 1999aPituitary &Drouin J Gauthier Y Lanctôt C, 1997Thebicoid-relatedhomeoprotein &Drouin J Lamolet B Lanctôt C, &Drouin J Gauthier Y Therrien M, Lamonerie T, Tremblay JJ, Lanctôt C, 2004 Guillemot F, &Drouin J Tsai MJ Chu K, Poulin G, Lamolet B, Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Pulichino AM, Brue T, Lamolet B, 2002GlucocorticoidreceptorsandCushing’s disease. Lamberts SWJ Otero- Yamashita M, Lopez-Leal R, Nasif S, deSouza FS, Lam DD, http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0289 Thematic Review 46523–46532. ofBiologicalChemistry and mediateshormoneaction.Journal 2003aTheT-boxDrouin J factorTpitrecruitsSRC/p160coactivators Biology as anovelmechanismforgeneactivation. MolecularandCellular between membersoftheNursubfamilyorphannuclearreceptors development. andcraniofacial Rieger syndromegeneinleft-rightasymmetry 401 279–282.(doi:10.1038/45803) andtoothmorphegenesis. Nature cardiac positioningandpituitary 1999Pitx2regulateslungasymmetry, &Rosenfeld MG Belmonte JC jcem.84.10.6066) Clinical Endocrinology&Metabolism of tumors. Journal cells, corticotrophtumors,andmalignantpituitary expression ofthecellcycleinhibitorp27Kip1innormalcorticotroph . 1999Low Monson JP, et al Jenkins PJ, Besser GM, Clayton RN, Metabolism diagnosis ofCushing’s ofClinicalEndocrinology& syndrome.Journal me.2007-0567) POMC. dependence onNurREandEboxNeuroforexpressionofpituitary outcome. predictive valueofdirect/indirectDNArecruitmentfortranscription me.2010-0422) corticotrope cells.MolecularEndocrinology specific enhancerofthePOMCgenewithpreferentialactivityin gene. Hindlimb patterningandmandibledevelopmentrequirethePtx1 140 1416–1422.(doi:10.1210/endo.140.3.6549) development.Endocrinology differentially expressedduringpituitary 124 2807–2817. differentiates posteriorfromanteriorlateralmesoderm.Development and Ptx1 definesthemostanteriordomainofembryo Development in transcriptionofpro-opiomelanocortin(POMC)gene.Genes& 1996 PTX1,abicoid-relatedhomeoboxtranscriptionfactorinvolved (doi:10.1210/me.2003-0127) corticotroph differentiation.MolecularEndocrinology Tpit-independent functionofNeuroD1(BETA2) inpituitary 8674(01)00282-3) homeoproteins. Tpit, activatesPOMCtranscriptionincooperationwithPitx cell-restrictedT-box 2001Apituitary Drouin J factor, Enjalbert A & 7207(02)00280-0) Molecular andCellularEndocrinology 11 e1004935.(doi:10.1371/journal.pgen.1004935) pomc expressionaboveacriticalfunctionalthreshold.PLoSGenetics Partially redundantenhancerscooperativelymaintainMammalian . 2015 Wardlaw SL, et al Mercer AJ, Corchon V, Sampath H, Meece K, Development 19 7549–7557.(doi:10.1128/MCB.19.11.7549) Molecular Endocrinology Molecular Cell 20 1539–1560.(doi:10.1210/jcem-20-12-1539) 10 1284–1295.(doi:10.1101/gad.10.10.1284) Nature (doi:10.1074/jbc.M305626200) Cell 126 1805–1810. 104 849–859.(doi:10.1016/S0092- 401 276–278.(doi:10.1038/45797) 47 38–49.(doi:10.1016/j.molcel.2012.04.021) 22 1647–1657.(doi:10.1210/ 84 3823–3830.(doi:10.1210/ 197 69–72.(doi:10.1016/S0303- j

Printed inGreatBritain 18 995–1003. 278 Nudi M, Ouimette JF & Drouin J 2005Bonemorphogenicprotein &Drouin J Ouimette JF Nudi M, Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P & Gauthier Y, Hugo P Maira MH, Gingras R, Lesage S, Philips A, Kawaguchi K, Ferrau F, Nusser C, Theodoropoulou M, Perez-Rivas LG, 2010Pomc-expressingprogenitors &Zeltser LM Carmody JS Padilla SL, 2003Pitx3is Tovmasian LT, &Goff SP Nunes I, Burke RE Silva RM, Philips A, Maira MH, Mullick A, Chamberland M, Lesage S, Hugo P & Hugo P Lesage S, Chamberland M, Mullick A, Maira MH, Philips A, Poulin G, Turgeon B & Drouin J 1997NeuroD1/BETA2 Turgeon B contributesto &Drouin J Poulin G, Quentien MH, Delemer B, Papadimitriou DT, Souchon PF, Delemer B, Jaussaud R, Quentien MH, Tsai JP, Vallette-Kasic S, & Pulichino AM, Gauthier Y Couture C, Gauthier Y, Brue T, Couture C, Vallette-Kasic S, David M, Pulichino AM, 2000 &Drouin J Paradis FW Chamberland M, Lebel M, Poulin G, Nasif S, de Souza FS, Gonzalez LE, Yamashita M, Orquera DP, Gonzalez LE, deSouza FS, Nasif S, 2010Functionsforpro-opiomelanocortin-derivedpeptides Mountjoy KG 2005Protein: &Drouin J Gauthier Y Maira M, Bilodeau S, Martens C, Maira MH, Martens C, Batsche E, Gauthier Y & Drouin J 2003bDimer- &Drouin J Gauthier Y Batsche E, Martens C, Maira MH, POMC generegulation Published byBioscientifica Ltd. 1329–1342. interference withPitx/Tpitactivity. MolecularEndocrinology (Smad)-mediated repressionofproopiomelanocortintranscriptionby E1861–E1870. 5946–5951. endocrine andlymphoidcells.MolecularCellularBiology 1997aNoveldimericNur77signalingmechanismsin Drouin J 1453) Endocrinology &Metabolism mutated inadenomascausingCushing’s ofClinical disease.Journal . 2015Thegeneoftheubiquitin-specificprotease8isfrequently et al Beschorner R, RuedaFaucz F, Assie G, Wildemberg LE, Stratakis CA, nm.2126) feeding circuits. Nature Medicine give risetoantagonisticneuronalpopulationsinhypothalamic PNAS required fordevelopmentofsubstantianigradopaminergicneurons. 5952–5959. receptor forcontroloftranscription.MolecularandCellularBiology 1997bAntagonismbetweenNur77andglucocorticoid Drouin J Biology cell-specific transcriptionofthePOMCgene.MolecularandCellular Metabolism ofClinicalEndocrinology& deficiency andsevereinfections.Journal deficiency (DAVID) inchildrenpresentingwithadrenocorticotropin functionandvariableimmune 2012 Deficitinanteriorpituitary . et al Galon-Faure N, Reynaud R, Jullien N, Munzer M, Pagnier A, gad.1065703) differentiation. cell 2003bTpitdeterminesalternatefatesduringpituitary Drouin J gad.1065603) deficiency. ACTH and mouseTpitgenemutationscauseearlyonsetpituitary . 2003aHuman et al DeVroede M, Van Vliet G, Deal C, Malpuech G, 4837.2000) and CellularBiology transcription factorsandhomeoproteinsofthePitxfamily. Molecular Specific protein:proteininteractionbetweenbasicHelix-Loop-Helix food intakeandadiposityinadulthood.PNAS hypothalamic melanocortinneuronsandiscriticalfornormal 2015Islet1specifiestheidentityof &Rubinstein M Low MJ (doi:10.1042/BJ20091957) in obesityanddiabetes.BiochemicalJournal (doi:10.1210/me.2004-0333) glucocorticoid receptor. MolecularEndocrinology subfamily ofNGFI-B/Nur77orphannuclearreceptorsand protein interactionsandtranscriptionalantagonismbetweenthe MCB.23.3.763-776.2003) recruitment. the proteinkinaseApathwayandAF-1-dependentcoactivator specific potentiationofNGFI-B(Nur77)transcriptionalactivityby 100 4245–4250.(doi:10.1073/pnas.0230529100) 17 6673–6682.(doi:10.1128/MCB.17.11.6673) Genes &Development 97 E121–E128.(doi:10.1210/jc.2011-0407) (doi:10.1210/me.2004-0425) (doi:10.1128/MCB.17.10.5946) (doi:10.1128/MCB.17.10.5952) Molecular andCellularBiology (doi:10.1073/pnas.1500672112) Genes &Development 20 4826–4837.(doi:10.1128/MCB.20.13.4826- 100 E997–E1004.(doi:10.1210/jc.2015- Downloaded fromBioscientifica.com at09/25/202110:03:15AM 17 711–716.(doi:10.1101/ 16 403–405.(doi:10.1038/ 17 738–747.(doi:10.1101/ 23 763–776.(doi:10.1128/ 428 305–324. 56 19 885–897. : 4 112

17 T111

17 via freeaccess Journal of Molecular Endocrinology Treisman J, Gonczy P, Vashishtha M, Harris E & Desplan C 1989 A single 1989Asingle Treisman J, Gonczy P, &Desplan C Harris E Vashishtha M, 1993Cell-specifichelix-loop-helixfactor required &Drouin J Therrien M Therrien M & Drouin J 1991 Pituitary pro-opiomelanocortin gene 1991Pituitary &Drouin J Therrien M Takayasu S, & Iwasaki Y, Yoshida M, Nigawara T, Kageyama K Asai M, Liu F, O’Connell SM, Kioussi C, Szeto DP, Ryan AK, Rodriguez-Esteban C, Smidt MP, van Schaick HS, Lanctôt C, Tremblay JJ, Cox JJ, van der Kleij AA, vander Kleij AA, Tremblay JJ, Cox JJ, Smidt MP, Lanctôt C, vanSchaick HS, Bitoun P, Reiter RS, Semina EV, Mintz-Hittner HA, Alward WLM, Ferrell RE, 1997 Isolationofanewhomeoboxgene Semina EV, &Murray J Reiter RS Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Osswald A, Theodoropoulou M, Hayakawa A, Sbiera S, Reincke M, factor(LIF) 1996Leukemiainhibitory &Melmed S Ray DW, Ren SG 2009TIF1beta/KAP-1is &Drouin J Balsalobre A Desroches J, Rambaud J, Rubinstein M, Mortrud M, Liu B & Low MJ 1993Ratandmouse &Low MJ Liu B Mortrud M, Rubinstein M, Takayasu S, Balsalobre A, Langlais D, Couture C, Roussel-Gervais A, Figarella- Berthelet F, Vallette S, Lacroix A, Bilodeau S, Roussel-Gervais A, Hausch F, Buchfelder M, Sattler M, Freiburger L, Kozany C, Riebold M, DOI: 10.1530/JME-15-0289 http://jme.endocrinology-journals.org Thematic Review proteins. amino acidcandeterminetheDNAbindingspecificityofhomeodomain and CellularBiology expressionofthepro-opiomelanocortingene. Molecular for pituitary MCB.11.7.3492) elements. expression requiressynergisticinteractionsofseveralregulatory (doi:10.1159/000258691) AtT20 corticotrophcells.Neuroimmunomodulation cytokine-induced transcriptionofproopiomelanocortingenein 2010Involvementofnuclearfactor-kBandNurr-1in Suda T 484–494. development.Genes&Development morphogenesis andpituitary the Bicoid-relatedhomeodomainfactorPitx1inspecifyinghindlimb 1999Roleof &Rosenfeld MG Izpisua-Belmonte JC Gleiberman AS, neurons. has highlyrestrictedbrainexpressioninmesencephalicdopaminergic 1997 AhomeodomaingenePtx3 &Burbach JP Wolterink G, Drouin J and ASMD.Nature Genetics gene 1998Anovelhomeobox &Murray JC Daack-Hirsch S Funkhauser C, Human MolecularGenetics and mappingtotheaphakiaregiononmousechromosome19. belonging tothePitx/Riegfamily:expressionduringlensdevelopment Cushing’s disease.Nature Genetics . 2015MutationsinthedeubiquitinasegeneUSP8cause et al Beuschlein F, Meitinger T, Saeki Y, Mizuno-Yamasaki E, Kawaguchi K, Investigation corticotroph cellline.RoleofSTAT pathway. ofClinical Journal stimulates proopiomelanocortin(POMC)expressionina M809023200) of BiologicalChemistry a coactivatoroftheorphannuclearreceptorNGFI-B/Nur77.Journal mice. glandbutnottothehypothalamusoftransgenic to thepituitary proopiomelanocortin genesequencestargettissue-specificexpression Endocrinology &Metabolism ofClinical corticotrope growthandCushingdisease.Journal The Cables1geneinglucocorticoidregulationofpituitary 2016 &Drouin J Brue T Figarella-Branger D, Zukerberg LR, Rueda BR, 1835–1845. tumorigenesis.MolecularEndocrinology and p27Kip1inpituitary 2010CooperationbetweencyclinE &Drouin J Brue T Branger D, Cushing disease.Nature Medicine glucocorticoid sensitivityandrelievesamouseallograftmodelof 2015AC-terminalHSP90inhibitorrestores &Paez-Pereda M Stalla GK is mutated in families with autosomal-dominant cataracts PITX3 ismutatedinfamilieswithautosomal-dominantcataracts Neuroendocrinology Cell PNAS (doi:10.1101/gad.13.4.484) Molecular andCellularBiology (doi:10.1210/me.2010-0091) 97 1852–1859.(doi:10.1172/JCI118615) 59 553–562.(doi:10.1016/0092-8674(89)90038-X) 94 13305–13310.(doi:10.1073/pnas.94.24.13305) 13 2342–2353.(doi:10.1128/MCB.13.4.2342) 284 14147–14156.(doi:10.1074/jbc. 58 373–380.(doi:10.1159/000126566) 6 19 167–170.(doi:10.1038/527) 2109–2116.(doi:10.1093/hmg/6.12.2109) 101 513–522.(doi:10.1210/jc.2015-3324) 21 276–280.(doi:10.1038/nm.3776) 47 31–38.(doi:10.1038/ng.3166) j

Printed inGreatBritain 17 88–96. 24 13 Yang G, Lim CY, Li C, Xiao X, Radda GK, Li C, Cao X & Han W 2009 2009 &Han W Cao X Li C, Radda GK, Yang G, Xiao X, Lim CY, Li C, van denMunckhof P, &Drouin J Lévesque D Gilbert F, Chamberland M, Young JI, Otero V, Cerdan MG, Falzone TL, Chan EC, Low MJ & Low MJ Young JI, Chan EC, Otero V, Falzone TL, Cerdan MG, Zhang F, Tanasa B, Merkurjev D, Lin C, Song X, Li W, Tan Y, Song X, Zhang F, Lin C, Tanasa B, Liu Z, Merkurjev D, 2013 &Cui S Li YQ Luo HS, Liu XF, Liu JL, Chen J, Lin JK, Zhang N, Vallette-Kasic S, Couture C, Balsalobre A, Gauthier Y, Metherell LA, Gauthier Y, Metherell LA, Balsalobre A, Couture C, Vallette-Kasic S, David M, Barlier A, Gueydan M, Brue T,Vallette-Kasic S, Pulichino AM, van den Munckhof P, Luk KC, Sainte-Marie L, Montgomery J, Montgomery J, van denMunckhof P, Sainte-Marie L, Luk KC, Tremblay Y, Tretjakoff I, Peterson A, Antakly T, Zhang CX & Drouin J Tremblay Y, &Drouin J Antakly T, Zhang CX Tretjakoff I, Peterson A, 1999Egr-1isadownstreameffectorofGnRH Tremblay JJ &Drouin J Tremblay JJ, Marcil A, Gauthier Y & Drouin J 1999 Ptx1 regulates SF-1 1999Ptx1regulatesSF-1 &Drouin J Gauthier Y Tremblay JJ, Marcil A, activatorof 1998Thepan-pituitary &Drouin J Tremblay JJ, Lanctôt C Vallette-Kasic S, Figarella-Branger D, Grino M, Pulichino AM, Dufour H, Dufour H, Pulichino AM, Grino M, Figarella-Branger D, Vallette-Kasic S, 2000Transcriptional &Drouin J propertiesof Tremblay JJ, Goodyer CG Accepted Preprint published online 20 January 2016 Accepted Preprintpublishedonline 20January 2016 Accepted 20January 2016 Received infinalform14January POMC generegulation Published byBioscientifica Ltd. of BiologicalChemistry activity byblockingSTAT3 interactionwithspecificityprotein1.Journal FoxO1 inhibitsleptinregulationofpro-opiomelanocortinpromoter Neurochemistry L-dopa inaphakiamice,amodelofParkinson’s of disease.Journal 2006 Striatalneuroadaptationandrescueoflocomotordeficitby Neuroscience of hypothalamic andhindbrainneuronsoftransgenicmice.Journal regulated expressionofpro-opiomelanocortingenomicfragmentsin 1998Authenticcell-specificanddevelopmentally Rubinstein M 1380–1385. corticotrope promoter-pausingrepressionprogram.PNAS . 2015Enhancer-boundLDB1regulatesa et al Ohgi KA, Zhang J, Biological Chemistry of expression bytargetingmitogen-activatedproteinkinase8.Journal releasing factor(CRF)regulatingpro-opiomelanocortin(POMC) MicroRNA 375mediatesthesignalingpathwayofcorticotropin- 3050–3056. 3991–3999. ofClinicalEndocrinology&Metabolism protein interactions.Journal associated withisolatedACTHdeficiencyinterferesinprotein: 2007TheTPITgenemutationM86R &Drouin J Dattani M Endocrinology &Metabolism ofClinical neonatal death,explainedbyTPITgenemutations.Journal isolated adrenocorticotropindeficiency:anunderestimatedcauseof . 2005Congenital Déchelotte P, et al Malpuech G, Deal C, Nicolino M, neurons. ofasubsetmidbraindopaminergic activity andforsurvival 2003Pitx3isrequiredformotor &Drouin J Sadikot AF Blanchet PJ, 8890–8894. proopiomelanocortin fusiongeneintransgenicmice.PNAS expressionandglucocorticoidregulationof 1988 Pituitary-specific Biology luteinizing hormone?genetranscription.MolecularandCellular and synergizesbydirectinteractionwithPtx1SF-1toenhance domain. activity byaninteractionthatmimicstheroleofligand-binding mend.12.3.0073) gene Lim3/Lhx3.MolecularEndocrinology and Pit1isanupstreamregulatoroftheLim-homeodomain homeobox1),actsinsynergywithSF-1 transcription, Ptx-1(pituitary corticotrophs. (TPIT), anewmarkerofnormalandadenomatoushuman transcriptionfactor of proopiomelanocortinandpituitary-restricted 2003Differential regulation &Brue T Drouin J Grisoli F, Enjalbert A, (doi:10.1159/000054547) Ptx1 andPtx2isoforms.Neuroendocrinology 19 2567–2576.(doi:10.1128/MCB.19.4.2567) EMBO Journal Development (doi:10.1210/jc.2008-1102) (doi:10.1210/jc.2002-021934) (doi:10.1210/jc.2007-0284) (doi:10.1073/pnas.85.23.8890) 18 6631–6640. Journal ofClinicalEndocrinology&Metabolism Journal 96 160–170.(doi:10.1111/j.1471-4159.2005.03522.x) 288 10361–10373.(doi:10.1074/jbc.M112.425504) 284 3719–3727.(doi:10.1074/jbc.M804965200) 130 2535–2542.(doi:10.1242/dev.00464) 18 3431–3441.(doi:10.1093/emboj/18.12.3431) 90 1323–1331.(doi:10.1210/jc.2004-1300) Downloaded fromBioscientifica.com at09/25/202110:03:15AM 12 428–441.(doi:10.1210/ 71 277–286. 56 : 4 112 88 85 T112

92 via freeaccess