Molecular Analysis of B Lymphocyte Development and Activation

The B lymphocyte lineage represents an important paradigm for exploring the molecular mechanisms underlying cell fate specification, differentiation and cellular activation. In the past five years, major advances have been achieved in our understanding of the transcriptional control of early B cell development and terminal plasma cell differentiation. In addition new insights became available for the processes of B cell activation, class switch recombination and somatic hypermutation. Many of the new findings and their implications for a molecular understanding of B cell biology in particular and cell differentiation in general are covered in this volume.

Zusammenfassung
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, andvaultedhertoapointofbreathtakingpotentialapotentialabruptly 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 partfrompredictablesourcesherkeenmindandbroadknowledgeit 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. Andtoseethesev

Inhalt
Gene Regulatory Networks Orchestrating B Cell Fate Specification, Commitment, and Differentiation.- Helix-Loop-Helix Proteins in Lymphocyte Lineage Determination.- Ikaros-Family Proteins: In Search of Molecular Functions During Lymphocyte Development.- Biochemistry of V(D)J Recombination.- The pre-B cell Receptor in B Cell Development: Recent Advances, Persistent Questions and Conserved Mechanisms.- Transcriptional Control of B Cell Activation.- Expression of MHC II Genes.- Class Switch Recombination: An Emerging Mechanism.- Blimp-1; Immunoglobulin Secretion and the Switch to Plasma Cells.- Wnt Signaling in Lymphopoiesis.