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