Molecular Analysis of B Lymphocyte Development and Activation

TheBlymphocytelineagerepresentsaleadingsystemforexploring- lecularmechanismsthatunderliecellfatespecification,differentiationand cellular activation. In the past five years major advances have been achievedintheanalysisofearlyBcelldevelopment,AIDdependentclass switchrecombinationaswellassomatichypermutationandBlimp-1re- latedplasmacelldifferentiation. Manyofthesefindingsandtheirimpli- tionsarecoveredinthisvolume. Twoemergentareasofresearchthatare includedinthecontributionsfocusonthepre-BCRandIkaros-familyp- teins. Thepre-BCRisanunusualmoleculardevicethatisusedtoexecute acriticaldevelopmentalcheckpointintheBlineage. Itsmechanismof- tion in relationto the pre-TCR and the mature antigen receptors (BCR, TCR)isofconsiderableinterest. Ikaros-familyproteinsappeartofunction viarecruitingtargetgenestodomainsofcentromericheterochromatinin the nucleus. Initially discovered in lymphocytes, they represent a novel system of gene regulationvia nuclearcompartmentalization. Finally, the volumeincludesachapteronWntsignalinginlymphopoiesis. Analysisof thisevolutionallyconservedpathwaywhichregulatescellularproliferation anddifferentiationindiversedevelopmentalcontextsbenefitedenormo- lyfromthediscoveryoftheLEF/TCFfamilyoffactorsinlymphocyticl- eages. ThisvolumeisdedicatedtothememoryofEugeniaSpanopoulou,ac- leagueandahighlyvaluedmemberofourscientificcommunity. Itc- tainsachapteronthebiochemistryofV(D)JrecombinationthatEugenia co-authoredwithDavidSchatz. Obituary Eugenia Spanopoulou was an extraordinary person and scientist. Her enormousintelligenceandenergysparkedimportantscientificdiscoveries, andvaultedhertoapointofbreathtakingpotential—apotentialabruptly erasedattheageof37withthecrashofSwissairflight111onSeptember 3,1998. Lostwithherwereherhusband,AndrewHodtsev,andyoungson, Platon. Eugeniawaspassionatelyinterestedinunderstandingthemolecular- sisofdevelopmentandchoseashermodelsystemthedevelopmentofB andTlymphocytes. Shebeganbystudyingthetranscriptionalregulation oftheTcell-specificgene,Thy-1,asagraduatestudentinFrankGrosveld s labatMillHill,London. Thereafter,sheturnedherattentiontothetopicof V(D)Jrecombination,firstasapostdoctoralfellowwithDavidBaltimore attheWhiteheadInstituteinCambridge,Massachusettsandsubsequently inherownlaboratoryatMountSinaiSchoolofMedicineinNewYorkCity. Eugeniamadefundamentaldiscoveriesconcerningthebiochemicalme- anismofthisreaction,andhowdefectsinitscentralenzymaticcom- nents,RAG1andRAG2,canleadtoahumanseverecombinedimmuno- ficiencydisorder,knownasOmennsyndrome. Atthetimeof herdeath, shehadbeenaHowardHughesMedicalInstituteinvestigatorforlessthan ayear,buthadalreadyassembledalaboratoryof15peopleworkingonan extensivearrayoftopicsinearlylymphocytedevelopmentandV(D)J- combination. Eugenialivedeachmomentofherlifewithanintensityfittingforthe cityinwhichshelived. LikeManhattan,shesleptlittle. Sheexpectedagreat dealofherself,andonlyalittlelessfromthosewithwhomsheworked. - geniaalsohadhighexpectationsforthescientificprocessandwasouts- keninherpraiseorcondemnationofthosewhometorfellshortofthose expectations. Shewasquicktoformanopinionanddevotedherselffe- ciouslytofriendshipsandhypotheses. PerhapsthegreatesttestimonytoEugeniaistheaffectionandreverence feltforherby themembersof herlab. Whilethisstemmedinnosmall partfrompredictablesources—herkeenmindandbroadknowledge—it founditsdeepestsourceinEugenia sabilitytotransmit,byexampleand word,her love of a life of learning and exploration. SandroSantigata,a graduatestudentinEugenia slab,capturedthiseloquentlyatthememorial serviceforEugeniaandAndrew,whenhesaid: VIII Obituary “Ifyouhaveeverbeenspellboundbyagreatstatue,enrapturedbyits strengthandvitality,enthralledbyitspurity,purposeandgraceandupli- edbythesenseofhopethatitsparkswithinyoursoul,thenyouhave- readyunderstoodwhyIadoredEugenia. Shesimplyembodiedtheideal- ticprinciplesthatformthecoreofadedicatedgraduatestudent sheart. Andtoseethesevaluesmaterializedintheformofone smentorcanbe nothingshortofinspirational. ” ListofContents GeneRegulatoryNetworksOrchestratingBCellFateSpecification, Commitment,andDifferentiation K. L. Medina·H. Singh. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Helix-Loop-HelixProteinsinLymphocyteLineageDetermination B. L. Kee. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Ikaros-FamilyProteins:InSearchofMolecularFunctions DuringLymphocyteDevelopment B. S. Cobb·S. T. Smale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 BiochemistryofV(D)JRecombination y D. G. Schatz·E. Spanopoulou. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Thepre-BcellReceptorinBCellDevelopment: RecentAdvances,PersistentQuestionsandConservedMechanisms M. R. Clark·A. B. Cooper·L. D. Wang·I. Aifantis. . . . . . . . . . . . . . . . . 87 TranscriptionalControlofBCellActivation L. M. Corcoran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 ExpressionofMHCIIGenes G. Drozina·J. Kohoutek·N. Jabrane-Ferrat·B. M. Peterlin. . . . . . . . . 147 ClassSwitchRecombination:AnEmergingMechanism A. L. Kenter. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Blimp-1;ImmunoglobulinSecretion andtheSwitchtoPlasmaCells R. Sciammas·M. M. Davis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 WntSignalinginLymphopoiesis A. Timm·R. Grosschedl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 ListofContributors (Theiraddressescanbefoundatthebeginningoftheirrespectivechapters. ) Aifantis,I. 87 Kohoutek,J. 147 Clark,M. R. 87 Medina,K. L. 1 Cobb,B. S. 29 Peterlin,B. M. 147 Cooper,A. B. 87 Schatz,D. G.