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*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*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...4 9 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.

From the Back Cover

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.

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