Gap Junctions in Development and Disease

288 Pages·2005·7.673 MB·English

by  Klaus Willecke, Jürgen Eiberger (auth.), Professor Dr. Elke Winterhager (eds.)

Elke Winterhager (Ed.)
Gap Junctions in Development and Disease
Elke Winterhager (Ed.)
Gap Junctions in
Development
and Disease
With 47 Figures, 10 in Color
123
Professor Dr. Elke Winterhager
Medical Faculty of the
University Duisburg-Essen
Hufelandstr. 55
45122 Essen
Germany
e-mail: [email protected]
Library of Congress Control Number: 2005926503
ISBN-10 3-540-26156-7 Springer-Verlag Berlin Heidelberg New York
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Preface
These are challenging times for scientists characterizing signaling path-
waysoftheirspecialinterest,becausethetechniquesemployedtoanalyze
molecularfunctionsorinteractionshavedevelopedrapidlyinrecentyears.
Withregardtogapjunctions,molecularcloningofthedifferentconnexin
isoforms, sequencing of several vertebrate genomes, generation of mice
carryingmutationsofthedifferentconnexingenes,andtargetingofinher-
itedhumandiseasestomutatedconnexingeneshavegivencompletelynew
insights into this research field. The use of modern techniques has con-
tributedtospecifyingandbroadeningourknowledgeoftheseintercellular
channels. However, at the same time, more sophisticated new questions
have arisen. Just to mention some milestones in the history of gap junc-
tionresearch:thisspecialcell–cellcontactwasidentifiedasanintercellular
nexusbetweenadjacentcellsbyDeweyandBarrin1962andfurtherchar-
acterization of the structure of this intercellular channel in the following
yearsledtothewell-knownstructureofthetwohemichannels,eachcom-
posed of six connexin subunits which form a water-filled pore for the
exchangeofmolecules.Thegap-junctionworldbecamecomplicatedwith
theidentificationofdifferentconnexinproteins,startingwiththecloning
of connexin32 by David Paul in 1986 and hopefully ending with all the
known20membersinthehumanand21membersinthemousegenome.
Furthermore,theexistenceofatleast20differentchannelsinhumanswith
differentelectrophysiologicalpropertieshasbeenshownbyevidencethat
the channels can be composed of different connexin isoforms, leading to
modificationsoftheirchannelproperties.
Thedivergencyofthechannelshasevokedthequestionofwhetherthese
channelsformaredundantsystem,orarehighlyspecificinmediatingsignal
cascades.Toanswerthisquestionnumerousconnexinknockoutmicehave
beenestablished,startingwiththeconnexin43knockoutmousebyReaume
etal.in1995withtheunexpectedresultofaspecialheartdefect.
Thespecificfunctionoftheconnexinsindevelopmentandorganfunc-
tion has been evaluated by systemically knocking out the different con-
nexinsandthereplacementofoneconnexinbyanotherisoform,whichis
reviewedinthefirstchapterbyKlausWillecke.Sincethegapjunctionsare
indeedchannelsresponsibleforiontransportacrossadjacentcellborders
and the propagation of membrane electricity and Ca2+ waves, an inten-
VI Preface
sivefieldofgap-junctionphysiologyhasdeveloped,definingthedifferent
channelproperties.However,uptonow,itremainsanopenquestionasto
what types of molecules in what amounts are crossing this channel. The
regulationofdiscriminationbetweenthemoleculeswhichcouldpasswith
limitations through these channel pores is still under discussions. It has
always been puzzling that the channel properties exclusively could gov-
ernthespecifictissuefunctionsfoundinthedifferentmousemutants.In
particular,thehypothesisalreadypostulatedbyLoewensteininthe1960s,
stating that these channels are involved in growth control and thus re-
sponsiblefortumorigenesis,neverreallyfittheknownchannelproperties.
Meanwhile, it has become evident that several connexin functions could
bemediatedviaprotein–proteininteractionsattheC-terminusofthecon-
nexin.Thus,thereisaneedtodiscriminatebetweenchannelandprotein
function. Impairmentofdevelopment and diseasesneed not bebasedon
connexinmutations,butratheronwrongsignalingmediatedviaprotein–
proteininteractions at the C-terminus. Research ongapjunctions gained
muchmoresocialrespectwhenitbecameobviouswiththepublicationof
Bergoffen et al. (1993) that connexin32 mutations are responsible for the
X-linkedCharcotMarietoothdisease.Thisdiscoverywasfollowedbydis-
coveriesofseveralotherconnexinmutationswhichleadtospecificdiseases
inhumans.Themostimportantonesaredescribedhereinthisvolume.
In the meantime, it has become impossibleto cover all aspects of con-
nexin research. In this volume, we have focused on the role of connexin
channels in embryonic development and in the development of human
diseases.
This volume deals with connexin channel redundancy, specificity, cell
signaling,andconductivity,whichareresponsiblefordevelopmentalpro-
cessesandappropriateorganfunction.Althoughthesecontributionscan-
not completely answer the question why the loss or mutation in gap-
junction proteins leads to a specific phenotype, at least they describe the
directionofgap-junctionresearchandhowresearchwillproceedinfuture.
I would like to express my profound thanks to all the authors who
contributed the various chapters on their special topics. They did a great
job and it was a joy to collaborate with my colleagues while editing this
book.
ElkeWinterhager
Essen,February2005
Contents
1 ConnexinandPannexinGenesintheMouseandHumanGenome 1
KlausWillecke,JürgenEiberger,JuliavonMaltzahn
1.1 Introduction.................................................................. 1
1.2 ConnexinGenes ............................................................. 5
1.3 Pannexingenes .............................................................. 9
1.4 Outlook......................................................................... 10
References............................................................................. 11
2 EssentialRoleofGapJunctions
DuringDevelopmentandRegenerationofSkeletalMuscle 13
JuliavonMaltzahn,KlausWillecke
2.1 Introduction.................................................................. 13
2.2 DevelopmentofSkeletalMuscles....................................... 13
2.2.1 EmbryonicOriginofMyoblasts............................... 13
2.2.2 MyotubeFormationbyMyoblastFusion................... 15
2.2.3 CharacteristicsofPrimaryandSecondaryMyotubes.. 16
2.2.4 GapJunctionalIntercellularCoupling
DuringMyogenesis................................................ 16
2.2.5 ConnexinExpressionDuringFusionofMyoblasts...... 17
2.2.6 ConnexinExpressioninMyotubes........................... 19
2.3 RegenerationofAdultSkeletalMuscles.............................. 21
2.3.1 SatelliteCells ........................................................ 22
2.3.2 ConnexinExpressionDuringMuscleRegeneration .... 24
References............................................................................. 25
3 ConnexinsinCardiacDevelopment:
Expression,Role,andTranscriptionalControl 29
Daniel B. Gros, Sébastien Alcoléa, Laurent Dupays, Sonia Meysen,
MagaliThéveniau-Ruissy,
BirgitE.J.Teunissen,MartiF.A.Bierhuizen
3.1 Introduction.................................................................. 29
3.2 MultipleConnexinGenesAreExpressedintheHeart........... 30
3.2.1 TheCardiacConnexins .......................................... 30
VIII Contents
3.2.2 ExpressionPatternsofCardiomyocyte-RelatedCx43,
-40and-45intheAdultMouseHeart....................... 32
3.2.3 SpatiotemporalExpressionPatterns
ofCardiomyocyte-RelatedCx43,-40and-45
intheDevelopingMouseHeart................................ 34
3.3 RoleofCxsinHeartDevelopment..................................... 38
3.3.1 NoIntrinsicCardiomyocyte-Autonomous
RequirementforCx43DuringHeartDevelopment ..... 38
3.3.2 Cx40isInvolvedintheSeptationProcess.................. 39
3.3.3 Cx45isRequiredfortheNormalProgress
ofCardiogenesis.................................................... 40
3.4 TranscriptionalControlofCardiomyocyte-RelatedCxs........ 41
3.4.1 StructureandRegulationoftheCx43Gene ............... 42
3.4.2 StructureandRegulationoftheCx40Gene ............... 45
3.4.3 StructureoftheCx45Gene ..................................... 49
3.5 Conclusions................................................................... 50
References............................................................................. 50
4 GapJunctionandConnexinRemodelinginHumanHeartDisease 57
NicholasJ.Severs,EmmanuelDupont,RiyazKaba,NeilThomas
4.1 Introduction.................................................................. 57
4.2 GapJunctionsandConnexinsinCardiomyocytes
oftheNormalHeart........................................................ 58
4.3 AlterationsinGapJunctionsandConnexinExpression
inHeartDisease............................................................. 61
4.4 VentricularMyocardiuminDisease................................... 62
4.4.1 StructuralRemodeling........................................... 62
4.4.2 RemodelingofConnexin43Expression..................... 64
4.4.3 RemodelingofExpressionofConnexin45
andConnexin40.................................................... 68
4.5 Short-TermEffectsofIschemia......................................... 69
4.6 RemodelingofGapJunctionsandConnexinExpression
inDiseasedAtrialMyocardium......................................... 70
4.7 SignificanceofConnexinCo-Expression:NewTools............ 72
4.8 ConcludingComment ..................................................... 76
References............................................................................. 76
5 GapJunctionExpressioninBrainTissues
withFocusonDevelopment 83
RolfDermietzel,CarolaMeier
5.1 GapJunctionsandNeurogenesis:SomeBasicAspects.......... 83
Contents IX
5.2 SegregationofConnexinExpression
DuringBrainDevelopment .............................................. 88
5.2.1 PrenatalExpression............................................... 88
5.2.2 PostnatalExpression.............................................. 90
5.3 DrawingaGeneralSchemeofGapJunctionFunction
intheDevelopingBrain................................................... 92
5.4 PitfallsinDefiningCell-SpecificExpressionofConnexins
inBrainTissues.............................................................. 94
5.5 SegregationofConnexinsDuringGlialLineaging................ 95
5.5.1 TheOligodendrocyticLineage................................. 95
5.5.2 TheAstrocyticLineage........................................... 98
5.6 UpstreamEventsRegulatingConnexinExpression.............. 100
References............................................................................. 102
6 ConnexinsResponsibleforHereditaryDeafness–
TheTaleUnfolds 111
MartineCohen-Salmon,FranciscoJ.delCastillo,ChristinePetit
6.1 Introduction.................................................................. 111
6.2 ConnexinGenesandHearingImpairment.......................... 112
6.2.1 CX26(GJB2)
andAutosomalRecessiveDeafnessDFNB1................ 112
6.2.2 CX26(GJB2)
andAutosomalDominantDeafnessDFNA3............... 118
6.2.3 CX30(GJB6)
andAutosomalDominantDeafnessDFNA3’.............. 119
6.2.4 OtherConnexinGenesandDeafness........................ 120
6.3 InnerEarandGapJunctions ............................................ 122
6.3.1 InnerEarArchitecture ........................................... 122
6.3.2 ConnexinExpressionintheCochlea ........................ 124
6.3.3 GapJunctionsandInnerEarHomeostasis................. 125
6.4 FutureProspects............................................................. 128
References............................................................................. 128
7 HumanConnexinsinSkinDevelopmentandSkinDisorders 135
GabrieleRichard
7.1 Introduction.................................................................. 135
7.2 TheGapJunctionSystemofHumanSkin........................... 136
7.2.1 ChangingPatternsofConnexinExpression
DuringHumanSkinDevelopment ........................... 136
7.2.2 ConnexinExpression
intheMatureHumanEpidermis.............................. 139
X Contents
7.2.3 ChangesinConnexinExpression
DuringEpidermalDifferentiation............................ 140
7.3 ConnexinDisordersoftheSkin ........................................ 142
7.3.1 ErythrokeratodermiaVariabilis............................... 146
7.3.2 PalmoplantarKeratodermas.................................... 151
7.3.3 EctodermalDysplasias........................................... 156
7.4 Summary....................................................................... 163
References............................................................................. 164
8 IntercellularCommunicationinLensDevelopmentandDisease 173
AdamM.DeRosa,FranciscoJ.Martinez-Wittinghan,
RichardT.Mathias,ThomasW.White
8.1 Introduction.................................................................. 173
8.2 ConnexinSpecializationintheLens .................................. 175
8.3 GeneticManipulationofLensConnexins........................... 177
8.3.1 KnockoutofCx43.................................................. 177
8.3.2 KnockoutofCx46.................................................. 179
8.3.3 KnockoutofCx50.................................................. 180
8.3.4 KnockinofCx46intotheCx50Gene ........................ 181
8.4 HowDoesCx46PreventCataract?..................................... 185
8.5 HowDoesCx50InfluenceLensGrowth?............................. 188
8.6 HumanConnexinMutationsCauseCataract....................... 190
References............................................................................. 191
9 ConnexinModulatorsofEndocrineFunction 197
PhilippeKlee,NathalieBoucard,DorothéeCaille,JoséCancela,
AnneCharollais,EricCharpantier,LaetitiaMichon,
CélinePopulaire,ManonPeyrou,RachelNlendNlend,
LaurenceZulianello,Jacques-AntoineHaefliger,PaoloMeda
9.1 Introduction.................................................................. 197
9.2 EndocrineCellsAreConnectedbySelectedConnexins ........ 199
9.3 DifferentEndocrineCells
ExpressDifferentConnexinPatterns ................................. 201
9.3.1 CellsProducingPeptideHormones.......................... 201
9.3.2 CellsProducingGlycoproteinHormones................... 207
9.3.3 CellsProducingSteroidHormones........................... 207
9.3.4 CellsProducingCatecholamines.............................. 208
9.3.5 CellsProducingPheromones................................... 209
9.4 SomeEndocrineCellsShareConnexinswithTheirTargets... 209
9.5 NonsecretoryFunctionsofConnexinsinEndocrineGlands.. 210
9.6 HormonesandConnexins................................................ 212
9.7 TheFuture..................................................................... 213
References............................................................................. 215
Contents XI
10 RolesofGapJunctionsinOvarianFolliculogenesis:
ImplicationsforFemaleInfertility 223
GeraldM.Kidder
10.1 Introduction.................................................................. 223
10.2 OvarianFollicleDevelopment........................................... 224
10.3 ConnexinsinDevelopingFollicles..................................... 225
10.4 RolesofIndividualConnexinsinFolliculogenesis................ 228
10.5 ConnexinRedundancyinOvarianFollicles ........................ 232
10.6 ImplicationsforUnderstandingHumanFemaleInfertility.... 233
10.7 Conclusions................................................................... 234
References............................................................................. 235
11 PlacentalConnexinsofMiceandMen 239
CarolineDunk,MarkKibschull,AlexandraGellhaus,
ElkeWinterhager,StephenLye
11.1 Introduction.................................................................. 239
11.1.1 TemporalandSpatialPatternofConnexins
inPlacentaeofMiceandMen.................................. 241
11.2 TheRoleofGapJunctionConnexinsintheMurinePlacenta. 241
11.2.1 Connexin26FacilitatesTransport
AcrossthePlacentalBarrier.................................... 242
11.2.2 Connexin31RegulatesMurineTrophoblast
CellLineageDevelopment....................................... 243
11.2.3 TSCellsasaModeltoInvestigatetheRole
ofConnexinsinPlacentalDevelopment.................... 244
11.3 TheRoleofGapJunctionConnexinsintheHumanPlacenta. 246
11.3.1 Cx43SupportsVillousCytotrophoblastFusion
toFormSyncytium................................................ 246
11.3.2 ANovelRoleforCx43inIntracellularSignaling......... 247
11.3.3 Connexin40RegulatesHumanTrophoblast
ExtravillousCellLineageDevelopment..................... 248
11.4 AnalogousFunctionsofMurineandHumanConnexins
inPlacentalDevelopment................................................. 250
References............................................................................. 251
12 ConnexinsinGrowthControlandCancer 253
ChristianC.Naus,GaryS.Goldberg,WunCheySin
12.1 Introduction.................................................................. 253
12.2 ConnexinsandGapJunctions........................................... 255
12.3 GapJunctionsandTumorSuppression............................... 255
12.3.1 EndogenousExpressionofConnexinsinTumors....... 255
12.3.2 RegulationofEndogenousConnexinExpression........ 256