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CellularandphysicalmechanismsofbranchingmorphogenesisVictorD.Varnerand CellularandphysicalmechanismsofbranchingmorphogenesisVictorD.Varnerand

CellularandphysicalmechanismsofbranchingmorphogenesisVictorD.Varnerand - PDF document

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CellularandphysicalmechanismsofbranchingmorphogenesisVictorD.Varnerand - PPT Presentation

DepartmentofChemicalBiologicalEngineeringPrincetonUniversityPrincetonNJ08544USADepartmentofMolecularBiologyPrincetonUniversityPrincetonNJ08544USAAuthorforcorrespondencecelestenprinceton ID: 125106

DepartmentofChemical&BiologicalEngineering PrincetonUniversity Princeton NJ08544 USA.DepartmentofMolecularBiology PrincetonUniversity Princeton NJ08544 USA.*Authorforcorrespondence(celesten@princeton.

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CellularandphysicalmechanismsofbranchingmorphogenesisVictorD.VarnerandCelesteM.Nelson1,2,ABSTRACTBranchingmorphogenesisisthedevelopmentalprogramthatbuildstheramifiedepithelialtreesofvariousorgans,includingtheairwaysofthelung,thecollectingductsofthekidney,andtheductsofthemammaryandsalivaryglands.Eventhoughthefinalgeometriesofepithelialtreesaredistinct,themolecularsignalingpathwaysthatcontrolbranchingmorphogenesisappeartobeconservedacrossorgansandspecies.However,despitethismolecularhomology,recentadvancesincelllineageanalysisandreal-timeimaginghaveuncoveredsurprisingdifferencesinthemechanismsthatbuildthesediversetissues.Here,wereviewthesestudiesanddiscussthecellularandphysicalmechanismsthatcancontributetobranchingKEYWORDS:Pattern,Tension,Mechanicalstress,Proliferation,BifurcationIntroductionArborizedepithelialnetworksarefoundubiquitouslyintheorgansystemsofanimalsasdiverseasinsectsandmammals.Suchbranchedepithelialtubescreateconduitsthatpermittheflowandexchangeofgasesandfluidswithinthebody.Branchingmorphogenesisisthe DepartmentofChemical&BiologicalEngineering,PrincetonUniversity,Princeton,NJ08544,USA.DepartmentofMolecularBiology,PrincetonUniversity,Princeton,NJ08544,USA.*Authorforcorrespondence(celesten@princeton.edu) ©2014.PublishedbyTheCompanyofBiologistsLtdDevelopment(2014)141,2750-2759doi:10.1242/dev.104794 DEVELOPMENT budswerethenusedasproxiestoinvestigatethestimulatoryeffectsoflungmesenchymeonthebranchingepithelium.Inparticular,Wessellsandcolleaguessoughttodeterminewhetherlocalincreasesincellproliferationalongtheepitheliumaccompaniedtheformationofsupernumerarybuds(Goldinetal.,1984;GoldinandOpperman,1980;GoldinandWessells,1979;Wessells,1970).Althoughinitialexperimentsfailedtodetectsignificantspatialdifferencesintheincorporationoftritiatedthymidinealongtheepithelium(Wessells,1970),subsequentstudiesreportedlevelsofproliferationinsupernumerarybudsthatincreasedwithtime,aswellasdecreasingratesofproliferationintheadjacent(non-branching)trachealepithelium(GoldinandWessells,1979).Furthermore,agarosebeadsloadedwithepidermalgrowthfactor(EGF)stimulatedtheformationofsupernumerarybudswhentheywereplacedadjacenttothetrachealepitheliuminculturedembryonicchickenlungs(GoldinandOpperman,1980).Consistently,treatmentoftheseculturedexplantswiththeDNAsynthesisinhibitoraphidicolindisruptedtheformationofsupernumerarybuds(Goldinetal.,1984).Elevatedlevelsofproliferationwerealsoreportedinthemorphogeneticallyactivetipsofextendingbranchesinthemousesalivarygland(Bernfieldetal.,1972,1973),mammarygland(Bresciani,1968)and,muchmorerecently,inthedevelopingkidney(MichaelandDavies,2004).Takentogether,thesedataledearlyinvestigatorstoconcludethatlocalstimulationofepithelialcellproliferationwasinvolvedintheformationofnewbranches(Ettensohn,1985)(Fig.1A).Evenso,theobservationthatelevatedproliferationisconfinedtobranchtipsdoesnot,ingeneral,indicatethatdifferentialproliferationisthedrivingforcebehindbranchinitiation.Itremainspossiblethatpatternsofdifferentialgrowtharesimplyaconsequenceofbranchformation,andnottheactualunderlyingphysicalmechanism.Amongtheearlyinvestigators,GoldinandWessellswereparticularlycognizantofthispossibility,acknowledgingthat:Althoughitisevidentthatthecontinuinghighlevelofmitoticactivityintheinducedbudsisdue,insomesense,totheinfluenceofthebronchialmesenchyme,thereisnoclearevidencetosuggestthattheinitialoutpocketingofthebudfromthetrachealepitheliumwasachievedthroughanactivelocalizedstimulationofmitoticactivity(GoldinandWessells,1979).Clearsupportforamechanismbasedondifferentialgrowthwouldrequireevidenceofpatternedcelldivisionpriorto(orduring)branchinitiation,i.e.thepresenceofaproliferativeprecursorthatpresagestheemergenceofactualepithelialbuds.Tofurtherprobetheroleofdifferentialgrowthandproliferation,mesenchyme-freecultureassaysweredevelopedtoexaminetheeffectsofdifferentmesenchymalgrowthfactorsonepithelialproliferationandbranching.Whenembeddedinthree-dimensional(3D)gelsofreconstitutedbasementmembraneprotein,isolatedepithelialexplantsbranchinthepresenceofexogenouslyappliedgrowthfactors(NogawaandIto,1995;Qiaoetal.,1999).Explantedembryonicepithelium,forexample,brancheswhentreatedwithfibroblastgrowthfactor1(Fgf1)(Cardosoetal.,1997)orFgf10(Belluscietal.,1997).Thepatternsofproliferationobservedwithintheseculturesweresimilartothosereportedinintactorgans:spatialvariationsincellproliferationwerenotobserveduntilbrancheshadalreadyformed(Nogawaetal.,1998)andzonesofelevatedproliferationwererestrictedtothetipsofextendingbranches(Fig.1B).Theseresultsweresurprising,becauseitistypicallyassumedthatfocalpatternsofgrowthfactorexpressioninthemesenchymestimulateslocalizedproliferationintheairwayepithelium,butintheseexplantedculturestheappliedgrowthfactorsareubiquitous(Makarenkovaetal.,2009),andnomesenchymalpre-patternispresenttostimulateepithelialproliferationlocally.Mesenchyme-freebranchingisnotuniquetothedevelopingairwayepithelium;similarbranchingpatternshavebeenobservedduring3Dcultureofepitheliaisolatedfromthedevelopingsalivarygland(MoritaandNogawa,1999;NogawaandTakahashi,1991),kidney(Qiaoetal.,2001,1999)andlacrimalgland(Makarenkovaetal.,2009).Ineachoftheseculturesystemstoo,spatialpatternsofproliferationwerenotobserveduntilbrancheshadalreadyformed.Moreover,thesespatialpatterns,whenpresent,wereallsimilartopologically:elevatedproliferationwaslocalizedtothebranchtips.If,however,growthfactor-loadedbeadswereembeddedintothegeladjacenttomesenchyme-freeexplants,newepithelialbranchesextendedtowardtheselocalsourcesofgrowthfactor(Parketal.,1998;Weaveretal.,2000),andcellproliferationwaselevatedinthebranchesextendingtowardsthebead(Weaveretal.,2000).However,inthesestudies,patternsofproliferationwerenotreportedpriortobranchformation,soitisunclearwhetherdifferentialgrowthprecededbranchinitiation.Ineachoftheaforementionedstudies,investigatorsexaminedpatternsofproliferationinexplantsthatwerefixedatdifferentstagesofbranching.Recentadvancesinliveimaging,however,havemadeit Fig.1.Branchingviapatternedordifferentialcellproliferation.Differentialratesofcellproliferationhavebeenhypothesizedtoinducebranchinginanumberofdevelopingorgans,includingthelung,kidneyandsalivarygland.Ineachofthesecases,elevatedlevelsofproliferationhavebeenobservedinnascentepithelialbuds.(A)Asarepresentativeexample,thedevelopingmouselungisshown.Giventheobservedpatternsofproliferation,itisgenerallythoughtthatgrowthfactorexpression(blue)intheneighboringmesenchymestimulateslocalizedgrowth/cellproliferation(green)intheepithelium,whichinitiatestheformationofnewepithelialbranches.(B)Lungepithelialexplants,denudedofmesenchymeandembeddedin3Dgelsofreconstitutedbasementmembraneprotein,havealsobeenshowntobranchinculture.Hereagain,elevatedproliferationwasobservedinincipientbranches,butonlyafterthesebrancheshadalreadyformed.Noproliferativepre-patternwasobservedintheepitheliumpriortobranching. Development(2014)141,2750-2759doi:10.1242/dev.104794 DEVELOPMENT possibletoinvestigatethisprocessdynamically.Forexample,SchnatwinkelandNiswanderusedalineoftransgenicreportermiceexpressingGFP-taggedhistonesinairwayepithelialcellstoquantifypatternsofproliferationinculturedlungexplants(SchnatwinkelandNiswander,2013).Bydynamicallytrackingmitoticeventsfromtime-lapseimages,theauthorsreportedelevatedlevelsofproliferationduringtheformationoflateralbranches,butnotduringtheformationofterminalbifurcations.Inaddition,thealignmentoftheobservedcelldivisionswasfoundtovaryspatiallyalongtheepithelium.Thisorientedgrowth,whichismediatedbyERK1/2signaling,hasbeenshowntodramaticallyinfluencetheoverallmorphologyofthedevelopingmurineairways(Tangetal.,2011).Conversely,intheembryonicchickenlung,althoughspatialpatternsofproliferationwereobservedduringbranchformation,proliferationwasnotrequiredfortheinitiationofnewepithelialbuds(Kimetal.,2013).Giventheseseeminglycontradictorydataandtheinherentcomplexityofmorphogenesis,physicalmodelsarenecessarytoresolvethemechanicalcontributionofpatternedcellproliferationtobranchingmorphogenesis(Gleghornetal.,2013;Wyczalkowskietal.,2012).Inthisspirit,Kimandcolleaguesdevelopedacomputationalmodeltodeterminethephysicalroleofdifferentialgrowthduringmonopodialbranchinginthedevelopingchickenlung(Kimetal.,2013).Patternedproliferationwasmodeledusingacontinuummechanicaltheoryforfinitevolumetricgrowth(Rodriguezetal.,1994),whichdecomposedtheoveralldeformationofthetissueintoacomponentduetogrowthandacomponentduetoelasticdeformation.Thisapproachwasstrictlyfocusedonbehaviorsatthetissuelevel,andanycell-ormolecular-leveldetailswerelumpedintomodelparameters.Thisframeworkhasbeenusedtosimulateseveralmorphogeneticprocesses,includinghead-foldformation(Varneretal.,2010)andcardiaclooping(Shietal.,2014;Voronovetal.,2004).Importantly,theobservedpatternsofepithelialproliferationinthechickenlungwerenotsufficienttosimulatetheobservedchangesinepithelialmorphologyduringbranchingmorphogenesis(Kimetal.,2013).Thesecomputationaldatawerefurthersupportedbytheexperimentalobservationthatinhibitingcelldivisiondidnotdisruptbudformationinthedevelopingchickenlung,suggestingthatproliferationdoesnotdrivetheformationofbranchesinthisspecies.Similarcomputationalstudiesinthedevelopingmouselung(andotherbranchingsystems)arethuswarranted.Whetherornotdifferentialproliferationinitiatesbranching,oncebrancheshaveformeditisunclearhowdistalpopulationsofproliferatingcellsaremaintainedwithintheextendingepithelium.Inthemouselung,expressionofthetranscriptionfactorN-myc(MycnMouseGenomeInformatics)isrestrictedtothedistalepithelium,whereitisthoughttohelpmaintainthispopulationofproliferatingundifferentiatedcells(Okuboetal.,2005).TransgenicmiceoverexpressinganN-myc-EGFPfusionproteinexhibitexpandeddomainsofproliferatingcellswithattenuatedlevelsofcelldifferentiation.Thissuggestsaninterplaybetweentheregulationofcellproliferationanddifferentiationduringbranchingmorphogenesis.RecentevidencehasalsoimplicatedthemicroRNAclustermiR-17-92duringthisprocess,whichfunctionsinpartbyregulatingtheexpressionofretinoblastoma-like2(Rbl2/p130)(Luetal.,2007),whichisimportantforcellcyclecontrol.Bycontrast,distalpoolsofproliferatingcellsinthepancreasareregulatedbyreciprocalfeedbackbetweenRhoandMAPKsignaling(Petzoldetal.,2013).Finally,duringrenalbranching,time-lapsemicroscopyhasrevealedthatproliferatingcellsinbranchtipsdelaminatefromtheepitheliumanddividewithinthelumenbeforereincorporatingbackintotheepithelium(Packardetal.,2013).Thereincorporationofthesedividingcellscontributestocellintercalationinthebranchtips,whichisinvolvedinepithelialexpansionandbranchgrowth.Itremainstobeseenwhethersimilarsignalingnetworksandcellbehaviorsareusedtomaintainthedistalpopulationsofdividingcellsinotherspeciesandorgansystems.Thus,althoughtheepitheliumisclearlyproliferatingduringthebranchingmorphogenesisofmostepithelialtrees,arolefordifferentialproliferationinbranchinitiationstillremainshypothetical.InvasivebranchingOneofthebest-understoodmodesofbranchingmorphogenesisisthatofinvasivebranching,whereinthetipofanewepithelialbranchtranslocatesforwardintothesurroundingtissueviaaninvasivemigratoryprocess.Thecellthatoccupiestheleadingedgeofthisextendingbranch,theso-calledtipcellleadercell,oftenexhibitsanextendedmorphologythatischaracterizedbymembraneprotrusionsatitsinvasivefront.Thecellsthatlagbehindthetipcell,sometimesreferredtoasfollowercellstrailingcellsstalkcellsmaintaincadherin-mediatedadhesiontoeachotheraswellastothetipcell.InvasivebranchinghasbeenexaminedindetailatboththephysicalandgeneticlevelinstudiesofDrosophilatrachealmorphogenesis(Casanova,2007;Ghabrialetal.,2003;Schottenfeldetal.,2010;Uvetal.,2003),buthasalsobeeninvestigatedduringsproutingangiogenesisinthevertebratevasculature.Drosophilatrachealsystemisanetworkoftubesthatconductoxygenandothergasesfromthelarvalsurfacetothecellsdeepwithinthetissuesofthebody(Ghabrialetal.,2003).Thetracheahasthreegenerationsofbranches:primary,secondaryandterminal.Thetrachealsystemisunusualamongbranchingorgansinthatitdevelopsintoabranchednetworkfromastartingpopulationof20clusters(knownastrachealsacs,eachcontaining80epithelialcells),withoutcelldivisionorcelldeath(Ghabrialetal.,2003;Samakovlisetal.,1996).TheDrosophilaFGFhomologBranchless(Bnl)isexpressedfocallybyepidermalandmesodermalcellsadjacenttothetrachealsac(Fig.2A)inlocationswhereeachprimarybranchwillbud(Sutherlandetal.,1996).Bnlbindstoitsreceptor,theFGFreceptorhomologBreathless(Btl),whichisexpressedontheepithelialcellsandactsasachemoattractant,inducingasubsetofthe80cellstoformabud,organizeintoatube,migrateoutofthetrachealsacandformtheprimary(firstgeneration)branches(Klambtetal.,1992).GeneticanalysishasrevealedthatBnlspecifiestheleader:thecellwiththehighestamountofBtlsignalingbecomesthetipcell,producesthehighestlevelsoftheNotchligandDeltaandactivelypreventsitsneighborsfromacquiringtipcellfate Fig.2.Branchingviainvasion.CollectivecellmigrationdrivesbranchingmorphogenesisintheDrosophilatracheaandvertebratevasculature.(A)IntheDrosophilatrachea,theexpressionoftheFGFhomologBranchless(Bnl,green)specifiesthetipcell,whichinhibitstipcellphenotypeintheneighboringstalkcellsthroughDelta-Notchsignaling.ThecollectivemigratestowardthesourceofBnl.(B)Thiscollectivemigrationismediatedbyatleasttwotypesofmechanicalforce.Thetipcellinducestensileforces(redarrows)onthesurroundingtissue,andpullsthestalkcellsforward.Atthesametime,thestalkcellsintercalatewitheachother,andthesecellularrearrangementsgeneratesufficientpushingforces(bluearrows)tomovethecollectiveforward. Development(2014)141,2750-2759doi:10.1242/dev.104794 DEVELOPMENT vialateralinhibitionthroughNotchsignaling(GhabrialandKrasnow,2006;Llimargas,1999).Consistently,mathematicalmodelingofDelta/NotchsignalingintheprimarybranchcellsofDrosophilatracheasuggeststhatthismodeoflateralinhibitionincreasestherobustnessoftheBnl-mediatedselectionoftipcellphenotype(Koizumietal.,2012).Furthermore,Bnlactivatestheexpressionofgenessuchasblistered,whichencodetranscriptionfactorsthatarerequiredformorphogenesisofsecondaryandterminalbranchesandbranchfusion,respectively(Guilleminetal.,1996;Samakovlisetal.,1996).Ageneticscreenrecentlyidentified70genesthatarerequiredforthedevelopmentofthetrachealsystem(Ghabrialetal.,2011),inadditiontothe100orsogenesthathadbeenidentifiedpreviouslybyotherstudies.Thecurrentestimatedminimumnumberofgenesrequiredtoformanarborizedepitheliumisthus200,inadditiontogenesinvolvedincellsurvivalandhousekeeping.MorphogenesisoftheDrosophilatracheaisaformofcollectivecellmigration(Rørth,2009).LiveimaginghasrevealedthatBnlinducestipcellstoundergocytoskeletalreorganization,enrichingactinattheirbasalsurface(LebretonandCasanova,2014).BnlalsoinducestheactivationofRacandtheexpressionoffascin,anactin-bundlingproteinrequiredfortheformationoffilopodiaattheleadingedge(Okenve-RamosandLlimargas,2014).Bycontrast,thetrailingstalkcellsexhibithighlevelsofactinattheirapicalsurfaces(LebretonandCasanova,2014).Inadditiontothesecytoskeletalchanges,theprimarybranchappearstoextendintothesurroundingtissuethroughacombinationofphysicalforces(Fig.2B).Liveimagingoffluorescentlylabeledcellshasrevealedthatfilopodiaactivelyprotrudefromtheleadingedgeofthetipcellintothesurroundingtissue(Caussinusetal.,2008;Ribeiroetal.,2002).Theforcesgeneratedbythistipcellarethoughttoinduceamechanicalstrainandpullthestalkcellsforward,whilealsoinducingadditionalrearrangementsofthestalkcellswithrespecttoeachother,thusgivingrisetogeometriclengtheningofthebranch(Caussinusetal.,2008).Initially,thelumenoftheprimarybranchissurroundedbymultiplestalkcellsarounditscircumference.Thestalkcellswithinthisbranchthenrearrangetogenerateanepitheliuminwhichthelumenissurroundedbyasinglecell,anintercalationeventthatbothlengthensthebranchandreducesitscaliber.E-cadherinisactivelyreducedinthestalkcellsviaendocytosis(Shayeetal.,2008),whichfacilitatesintercalation,asdisruptingendocytictraffickingofE-cadherinblocksstalkcellintercalationandtrachealextension.Thisisconsistentwiththefindingthatgenesinvolvedinvesicletraffickingarerequiredfortrachealmorphogenesis(Ghabrialetal.,2011).Laserablationexperimentshavealsorevealedthatpullingforcesfromthetipcellarerequiredtoinducestalkcellintercalation(Caussinusetal.,2008):thestalkcellsaresubjectedtotensileforcesbythetipcellandablatingtheirconnectionwiththetipcellnotonlypreventssubsequentintercalation,butalsocausesthestalkcellstoretract.Howtensileforcesexertedbythetipcellleadtointercalationbythestalkcellsremainsunclear.Anobvioushypothesisisthatpullingbythetipcellactivatestheendocyticmachineryinthestalkcellsandtherebyreducesthecell-surfacelevelsofE-cadherin,thusincreasingadhesiondynamicsandfacilitatingintercalation.Thisprocessalsodependsonsignalingdownstreamoftheplanarcellpolarity(PCP)pathway,specificallyviaFrizzled,whichappearstoinducetheturnoverofjunctionalE-cadherinbyactivatingthesmallGTPaseRhoAviatheDrosophilaRhoguaninenucleotideexchangefactorRhoGEF2(Warringtonetal.,2013).RhoGEF2ispartofafamilythatincludesthemammalianp115-RhoGEFandLARG(MulinariandHacker,2010),thelatterofwhichisactivatedbytensionalforcesexertedonfocaladhesioncomplexesinmammaliancellsinculture(Guilluyetal.,2011).Furthermore,thelevelsofE-cadherinwithinthestalkcellsarealsocontrolledbysignalingthroughSrc:activatedSrcreducestheaccumulationofE-cadherinatthemembraneofstalkcells,permittingthemtointercalatewiththeirneighbors(Shindoetal.,2008).Srcactivationrespondstotension(Arthuretal.,2000),suggestingasecondpossiblepathwaybywhichtipcellscaninduceintercalationoftheirneighboringstalkcells.Together,thesefindingshighlightthatphysicalforcesarecrucialfortherepositioningofstalkcellsduringbranchelongation.ThephysicalandmolecularmechanismsofbranchingmorphogenesisintheDrosophilatracheaaresimilartothosethatdrivesproutingangiogenesisinthevertebratevasculature(Ochoa-EspinosaandAffolter,2012).Here,tipcellsareselectedbyadifferentligand,vascularendothelialgrowthfactor(VEGF)A,whichinducessignalingdownstreamofVEGFreceptor2(Vegfr2)toupregulatetheexpressionofDelta-like4(Dll4)(Hellstrometal.,2007;Noguera-Troiseetal.,2006;Suchtingetal.,2007).CellswiththehighestlevelsofDll4becometipcellsandleadthegrowingbranch(Jakobssonetal.,2010).ActivationofNotchsignalingintheadjacentcellsreducestheirexpressionofVegfr2,thusinducingthemtobecomestalkcells(Kume,2009).Moreover,thisNotch-mediatedinhibitionofthetipcellphenotypecanextendbeyondadjacentcells,asDll4canbeincorporatedintosmallextracellularvesiclesknownasexosomesthataretakenupbycellsatadistance(Sheldonetal.,2010)topreventthetipcellphenotypeandeveninduceretractionofacapillarysprout(Sharghi-Naminietal.,2014).AswiththeDrosophilatrachealsystem,computationalmodelshavealsolentsupporttothemodelofNotch-mediatedinhibitorysignalinginstalkcells(Bentleyetal.,2009),andhavesuggestedthatdrag(pulling)forcesfromthetipcellmaycontributetothissignalingpathway(Wangetal.,2013).Itwouldbeinterestingtouselaserablationtodisrupttheconnectionsbetweentipcellsandstalkcellsduringangiogenesistotestthephysicallimitsofthehomologybetweentrachealbranchinginfliesandangiogenicsproutinginvertebrates.EpithelialfoldingInotherdevelopingorgans,branchingepitheliadonotexhibitaninvasiveormigratoryphenotype.Instead,theepitheliumfoldsasacoherentsheet,andtheleadingedgeexhibitsneitherfilopodialnorlamellopodialprotrusions.Thisepithelialfoldingcanbedrivenbyactiveforcessuchasapicalconstrictionordifferentialgrowth,orbyexternalforcessuchasmechanicalbuckling(Taber,1995)(Fig.3),andhasbeenpostulatedtooccurinthedevelopingmammarygland(Ewaldetal.,2008)and,morerecently,intheembryonicmouselung(SchnatwinkelandNiswander,2013).Becausemanyofthesignalingpathwaysinvolvedinbranchingareconservedacrossorgansandspecies(Davies,2002),itisoftenassumedthatthephysicalmechanismsofmorphogenesisaresimilarlyconserved(Lubkin,2008).Inthelung,forexample,incipientbranchesextendtowardlocalizedregionsofFgf10expressedbytheadjacentmesenchyme(Belluscietal.,1997;Parketal.,1998).ThisisphenomenologicallysimilartothemolecularmechanismsthatregulatetrachealbranchinginDrosophila,wherebynewtrachealbranchesformascellsextendfilopodiaandmigratetowardfocalregionsofexpressionoftheFGFhomologBnl(MetzgerandKrasnow,1999;Sutherlandetal.,1996).Thismolecularhomologyhasledresearcherstospeculatethatasimilarmigratoryphenotypeunderpinsthemechanicsofairwaybranchinginthemammalianlung(MetzgerandKrasnow,1999;Sutherlandetal.,1996).ThishypothesisgainedgroundinthewakeofexperimentsdemonstratingthatisolatedepithelialexplantsextendbranchestowardFgf10-soakedbeadsin3Dculture(Park Development(2014)141,2750-2759doi:10.1242/dev.104794 DEVELOPMENT etal.,1998;Weaveretal.,2000).ItwasarguedthatFGFsexertachemoattractanteffectonthebranchingepithelium,butitremainsunclearhowthischemoattractionmanifestsitselfinthecontextofacoherentepithelium.Duringinvasivebranching,chemoattractiondrivesthedirectedmigrationofcellsintheepithelium(Sutherlandetal.,1996).Butduringepithelialfolding,iftheconstituentcellsarenotcrawlingtowardsalocalsourceofgrowthfactors,howdoestheepitheliumdeforminadirection-dependentmanner?Recentdatasuggestthatapicalconstrictionofcellsintheairwayepitheliumissufficienttoinitiatetheformationofmonopodial(lateral)branchesinthedevelopingchickenlung(Kimetal.,2013).Newepithelialbudsformalongthedorsalaspectoftheprimarybronchialtube,asairwayepithelialcellsconstricttheirapicesandadoptwedge-shapedprofiles.ThesecoordinatedchangesincellshapedrivedirectionalfoldingoftheairwayepitheliumviaaprocessthatisbothdependentonactomyosincontractionanddownstreamofFGFsignaling(Kimetal.,2013).Althoughepithelialproliferationisnotrequiredfortheformationofnewbuds,itisneededforthesubsequentstagesofbranchelongation.Thisissupportedbyevidencefromthedevelopingmouselung,whichsuggeststhatorientedcelldivisionintheairwayepitheliumisresponsibleforthedirectionalelongationofthesetubes(Tangetal.,2011).However,whetherapicalconstriction-mediatedbranchingoccursinthemouseorinanyotherspeciesremainstobedetermined.Inaddition,severalotherdevelopingorgans,includingthekidneyandmammarygland,branchvianon-invasivemechanisms;butthephysicalmechanismsthatdriveepithelialfoldinginthesesystemsremaintobeinvestigatedquantitatively.Ithasalsobeenhypothesizedthatmechanicalbucklingisinvolvedinthebranchingmorphogenesisofdevelopingepithelia(Ettensohn,1985).Inhisseminalreviewpaper,Ettensohnsuggestedthatepithelialgrowth,constrainedbythesurroundingmesenchyme,maycausetheepitheliumtobuckleinward,formingcleftsatseveralsites(Ettensohn,1985).Thispossibilityissupportedbyrecentreportssuggestingthatdifferentaspectsofgutmorphogenesis,includinggutlooping(Savinetal.,2011)andvillusmorphogenesis(Shyeretal.,2013),aregeneratedviamechanicalbuckling.Itwillbeinterestingtodeterminewhetherphysicalinstabilitiesdriveepithelialbranchingmorphogenesisinotherorgans.Matrix-drivenbranchingInmostdevelopingorgans,theepitheliumissurroundedbymesenchymalcellsaswellasbyextracellularmatrix(ECM).Notsurprisingly,therefore,theECMhasbeenshowntoplayaninstructiveroleinbranchinginvariouscontexts.AregulatoryrolefortheECMinbranchingmorphogenesiswasrecognizedmorethan30yearsago(WilliamsandDaniel,1983),andhasbeenmostdeeplyinvestigatedforthemorphogenesisofthesalivaryandmammaryglands.Inmice,oneofthethreepairsofmajorsalivaryglands,thesubmandibularglands,beginstodevelopatE11,whenthebulb-shapedanlagegrowsoutfromtheoralepitheliumandswellsintothesurroundingmandibularmesenchyme(Tucker,2007).Onedaylater,indentationsformonthesurfaceoftheepithelialbudandprogressinwardly,cleftingtheepitheliumintomultipledaughterbuds(Fig.4A).Atthesametime,proliferationoftheepithelialcellscausesthedaughterbudstoextend(Pateletal.,2006).Thisprocessrepeatsitselftoformthematuresalivaryepithelialtree,whichconsistsofclustersofterminalbudsconnectedtoasystemofductsthatdeliversalivatotheoralcavity(Harunagaetal.,2011).Branchingmorphogenesisofthesalivaryepitheliumhasbeenstudiedmostextensivelyincultureexvivo,byplacingthedevelopingglandontopoffilterpaperfloatingonmedium,duringwhichtimetheexplantcontinuestobranch(Borghese,1950;Grobstein,1953b,1956).Thisapproachrevealsthatcleftformationrequiresactomyosincontraction,astreatmentwithcytochalasinBdisruptsmorphogenesis(SpoonerandWessells,1970a,1972).Morerecently,time-lapseimaginganalysisofsalivarybranching Fig.3.Branchingviaepithelialfolding.Thecollectivefoldingofcellsinanepitheliumcanproducenewbranches.Changesinepithelialshapecanoccurby:(A)apicalconstrictionofcellswithinalocalizedregion(pink)oftheepithelium;(B)differentialgrowth,causedbyincreasedcelldivisionintheepithelium(pink)relativetoanadjacenttissue(white);or(C)mechanicalbuckling,whichcaststheepitheliumintoawave-likemorphologywhenloadedwithsufficientcompressiveforce,possiblyproducedbyadjacenttissues. Fig.4.Matrix-mediatedbranching.TheECMplaysaninstructiveroleinbranchingmorphogenesisinsomeorgans.(A)Inthesalivarygland,fibrilsoffibronectin(red)aredepositedatthesitesofnewclefts(gray)intheepithelium.(B)Inthemammarygland,fibrilsofcollagen(blue)presentwithinthestromamayactasguidancecuesfortheelongationofnascentepithelialbranches(red)duringmorphogenesis. Development(2014)141,2750-2759doi:10.1242/dev.104794 DEVELOPMENT hasshownthateachcleftfirstinitiatesasagapbetweenadjacentepithelialcells(KadoyaandYamashina,2010;Larsenetal.,2006),inaprocessthatappearstodependonERK1/2signaling(Koyamaetal.,2008)downstreamofEGFfromthesurroundingmesenchyme(Kashimataetal.,2000;NogawaandTakahashi,1991).Oncecleftshaveinitiatedonthesurfaceoftheepithelium,theyappeartobestabilizedwhentheepithelialcellsliningthecleftsformcell-ECMadhesionsthatcontainactivatedfocaladhesionkinase(FAK)(Daleyetal.,2011).Here,FAKappearstobeactingasamechanosensor,andisrequiredforthesubsequentassemblyofECMfibrilswithinthegrowingcleft.Thestabilizedcleftsthenprogressdeeperintotheepithelialbud(KadoyaandYamashina,2010)viaRho-associatedkinase(ROCK)-inducedactomyosincontraction,whichleadstotheassemblyoffibronectinfibrilsatthebasalsurfaceoftheepithelialcellsliningthegrowingcleft(Daleyetal.,2009).Cleftelongationisadynamicprocess(Harunagaetal.,2011),andtimelapseimagingsuggeststhatnotonlydotheepithelialcellsthemselvesmovedynamicallyatthebasalsurfaceofthegrowingbud(Hsuetal.,2013),butalsothatthegrowingendofthecleftwigglesastheadjacentepithelialcellsmoveandchangeshape(KadoyaandYamashina,2010).Smallcleftscanalsoregressafterinitiation,suggestingthatthesitesatwhichcleftsfirstformarenotdeterminedprecisely(Larsenetal.,2006).Furthermore,thespatialprogressionofacleftdeeperintotheepitheliummirrorstheincreaseincell-ECMadhesionsformedbytheepithelialcells,whichpreferentiallylosemembranelocalizationofE-cadherinintheseregions,denotingareductionincell-celladhesion(Sakaietal.,2003).Thepresenceoffibronectininthestabilizedcleftstimulatesintegrin-mediatedsignalingandproliferationoftheadjacentepithelialcells,whichhelpstodeepenthecleft(Daleyetal.,2009,2011).FibronectinalsoinducestheexpressionofBtbd7intheadjacentepithelialcells,whichinturnrepressesE-cadherinandactivatesSlug(Onoderaetal.,2010).EpithelialproliferationrequiressignalingthroughFGFreceptor1(Fgfr1)(Hoffmanetal.,2002)and,accordingly,inhibitingFgfr1kinaseactivitydisruptssalivarybranchingbyhaltingproliferation,althoughithasnoeffectontheinitiationofclefts.InhibitingROCK,myosinIIATPase,orFAKalsostallsbranchingaftercleftinitiation(Daleyetal.,2009,2011).E-cadherinprobablyalsoplaysasignalingrole,asitsassociationwiththeHippopathwayeffectorTAZ(transcriptionalco-activatorwithPDZ-bindingmotif)regulatesbranchingofsalivaryexplants(Engeretal.,2013).DynamicchangesinthelocalizationofECMproteinsthusappeartobecrucialforcleftinitiationandprogressionduringbranchingmorphogenesisofthemurinesubmandibulargland.Theepitheliumcontactsitsbasementmembraneduringsalivarydevelopment(BernfieldandBanerjee,1982),withECMturnoverbeinghigheratthedistalendsofthebudsthanwithinthestalks.Fibrilsofinterstitialcollagen(Fukudaetal.,1988;Nakanishietal.,1988)andfibronectin(Sakaietal.,2003)accumulatepreferentiallyatsitesofcleftinitiation,andexogenousfibronectinintheculturemediumissufficienttoinducecleftformationinsalivaryexplants.Consistently,theepitheliumincreasesitsexpressionofintegrins1and4duringthebranchingprocess,andinresponsetoEGF(KashimataandGresik,1997).Simultaneously,theepithelialcellsthemselvesalsomovedynamically,andapparentlyrandomly,withinthecleftingbud(Larsenetal.,2006;Weietal.,2007),butthemotilityofthosecontactingthebasementmembraneishigheranddependsonsignalingdownstreamofintegrins6and1,aswellasonmyosin(Hsuetal.,2013).EpithelialcleftingthusresultsfromthecombinedmovementofepithelialcellsandthetranslocationofECMfibrils.Althoughcleftformationappearstoberatheruniquetothedevelopingsalivarygland,fibronectinisalsorequiredforbranchingmorphogenesisofthelungandkidney(DeLangheetal.,2005;Roman,1997;Sakaietal.,2003).Fibronectinisexpressedduringthepseudoglandular(branching)stageofembryoniclungdevelopmentinmice(E11-E16),withhighestintensityoffibronectinstainingoccurringatbranchpoints(RomanandMcDonald,1992).Disruptingfibronectinassociationusingfunction-blockingantibodiesreducesbranchingofembryoniclungexplants,whereasexogenousadditionoffibronectinenhancesbranching(DeLangheetal.,2005;Sakaietal.,2003).Consistently,treatmentsthatcausemislocalizationoffibronectinfibrilsblockairwaybranching(Princeetal.,2005).Fibronectinisalsoimplicatedinbranchingmorphogenesisinthedevelopingkidney,wherefibronectinexpressionisenhancedinthemetanephricmesenchymeadjacenttothebranchinguretericbud,andinducesbranchingtubulogenesisofkidneyepithelialcells(SantosandNigam,1993)andembryonicuretericbudcells(Yeetal.,2004)inculture.Ourunderstandingofthephysicalroleoffibronectininthebranchingmorphogenesisofthelungandkidneyisstillrudimentary,butsomeofthefactorsinvolvedinfibronectin-dependentbranchinghavebeenuncovered.Inparticular,fibronectindepositionwasshowntoberegulatedbyWntintheembryoniclung(DeLangheetal.,2005).Whereasfibrilsoffibronectinappeartobisectthesalivaryepitheliumlikeacheesewire,theECMprovidesadifferenttypeofguidancecueforbranchingmorphogenesisofthemammarygland.Unliketheotherorgansdiscussedthusfar,themammaryglanddevelopsintoafullyelaboratedepithelialtreepostnatally,duringpuberty.Inmouseandhuman,theepithelialanlagepresentatbirthisasmallsimplybranchedrudiment,embeddedinacomplexmesenchymethatcontainsadiposeandfibrousregions(GjorevskiandNelson,2011).Theglandremainsquiescentuntiltheonsetofpuberty,atwhichtimehormonessuchasovarianestrogensinducerapidproliferation,expansionandbifurcationoftheepitheliumuntilitreachesthelimitsofthefatpad(Sternlichtetal.,2006).Theepithelialtreethusexpandsfromthenippletothemarginsofthemesenchyme,anddoessoalongthelongaxisofthefatpad(Brownfieldetal.,2013).RecentquantitativeimaginganalysisrevealedthatfibersoftypeIcollagenarepresentwithinthemousemammaryglandpriortotheonsetofpubertalbranching,withthemajorityofthesefibersorientedparalleltothelongaxisofthegland(Brownfieldetal.,2013).Importantly,epithelialbranchesorientthemselvesalongthecollagenfibersastheyextend(Fig.4B).Consistently,branchingincreaseswithcollagendensity(Nguyen-NgocandEwald,2013)andcollagenfibrilorientationissufficienttodirecttheangleofbranchelongationinculture(Brownfieldetal.,2013;Guoetal.,2012).Similarly,geneticmanipulationsinmicethatresultinadecreaseincollagensynthesisorassembly,suchasknockoutofmatrixmetalloproteinase(MMP)11(Tanetal.,2013),leadtodefectsinmammarybranching.Thesedatasuggestthatcollagenfibersactaspatterningcuesforbranchingmorphogenesisofthemammaryepithelium,althoughhowthesefibersthemselvesbecomepatternedremainsunclear.ThemammaryepitheliuminteractswithitssurroundingECMprimarilythrough1integrin.InbothcellcultureandinvivointegrinassociateswiththetransmembraneMmp14,andsilencingeitherofthesemoleculesinmammaryepithelialcellspreventsbranchingmorphogenesis(Morietal.,2013).Mmp14isexpressedathighlevelsbyepithelialcellslocatedwithintheterminalbudsofthepubertalmousemammarygland(Morietal.,2013),andisalsoexpressedathighlevelsbycellsatbranchsitesinculture(Morietal.,2009).Importantly,thetransmembrane/cytoplasmicdomainsofMmp14appeartobecrucialforitsinteractionwith1integrin 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andfordownstreamsignalingtoMAPK,whichinducesbranchinginthecollagen-richmicroenvironmentsurroundingthemammaryepithelium.Inadditiontoinducingsignaling,Mmp14alsodegradestheECMattheinvasivefrontofmammaryepithelialbranchesinculture,whichhasbeenpostulatedtoreducethestericand/ormechanicalresistanceofthesurroundingmatrixtoexpansionbytheepithelium(Alcarazetal.,2011).Giventheabove-mentionedreportsofmammaryepitheliumextendingalongcollagenfibersinvivoandinculture,amorelikelypossibilityisthatMmp14helpstheepitheliumtoremodelthesurroundingECMasthecellsfindtheirmechanicalguidancecues.Recentdatasuggestthatmechanicalstressesexertedbythemammaryepitheliumarealsocrucialfordirectingbranchingmorphogenesis,aswellasforinitiatingnascentbranches(GjorevskiandNelson,2010,2012).Individualcellscontractisometricallywithinthemammaryepithelium,andthestressesgeneratedbythiscontractionbecomeconcentratedatspecificsitesalongtheepithelialtree,dependingonitsgeometry(GjorevskiandNelson,2010).Newbranchesinitiateatsitesofhighestmechanicalstress,andthisbranchinitiationisstimulatedinpartbylocalactivationofFAKwithinthesecells.Themechanicalproperties(elasticmodulusandcrosslinking)ofthesurroundingECMregulatetheprofileofmechanicalstressandbranchinitiation(GjorevskiandNelson,2010),andarealsoaffectedbymatrixremodelinginducedbycontractionoftheepithelium(GjorevskiandNelson,2012).SuchECM-mediatedmechanicalstressesregulatetheexpressionofmesenchymalgenes,includingthoseencodingtranscriptionfactorssuchasSnailandSlug,withinbranchsites(Leeetal.,2011).Asthesegenesarealsoexpressedatbranchsiteswithinthemammaryinvivo,itispossiblethattheyareinducedbythecollagenfibrilsalreadypresentinthemesenchyme.ConclusionsInsummary,recenttimelapseimaging,quantitativemorphometricanalysisandcomputationalmodelshavetogetherrevealedthatbranchingmorphogenesisisnotasinglephysicalprocess.Instead,agroupofseveraldifferentphysicalmechanismscanallgeneratebranchedepithelialtrees.Itisimportanttonotethatthesemechanismsarenotmutuallyexclusive,andmayindeedbefoundtoactsynergisticallyduringbranching.Furthermore,theexactmechanismsthatdrivemorphogenesisofmanybranchingepitheliaremaintobeelucidated.Basedonourdiscussionsabove,weidentifyfourmajorconclusionsthatwedetailbelow.Thepatternofbranchingdependsonapre-patternwithinthesurroundingmesenchymeordoesit?Mostmodelbranchingsystemsshowsomeevidenceofacomplementarypatternofgeneexpressionorphysicalfactorsinthemesenchymepriortobranchinitiation.Focalexpressionofgrowthfactorsisthemostcommonmesenchymalpre-pattern,butthealignedfibrilsofcollageninthestromaofthemammaryglandalsolendsupporttotheideaofphysicalpre-patterningofbranchingmorphogenesis.However,theoneproblemwiththisconceptcomesfrommesenchyme-freeculturemodels,whichundergobranchingmorphogenesisintheabsenceofanypre-patternedsignal.Eitherthelattermodeldoesnotreflectthesituationinvivo,orthereissomeelementofself-assemblytothepre-patterningprocess.Eitherway,wearestillleftwithglaringquestions.Whatinducesthepre-patternofsignalinthemesenchyme?Howdoesthisarise,bothspatiallyandtemporally,duringdevelopmentofthebranchingepithelialtree?Whatfeedbackmechanismsareneededtocouplethemesenchymalpre-patterntotheelaborationoftheepithelium?Computationalmodelsmayprovidesomeguidanceinaddressingthislastquestion(IberandMenshykau,2013;Rayetal.,2013),whichischallengingtoinvestigateexperimentallyusingintactorgans.BranchesareunlikelytoformduetospatialpatternsinproliferationMorethan40yearsofinvestigationhavefailedtoyieldincontrovertibleevidencethatlocalincreasesinthegrowthofanepitheliumcangenerateanewbranch.Clearly,proliferationisnecessarytoincreasethenumberofcellswithinthebranchonceithasformedandtopromotebranchextension(atleast,inorgansotherthantheDrosophilatrachea).Intriguingly,acrossalargenumberofvertebrateorgans,thisincreaseinproliferationisconcentratedatthetipofthegrowingbranch.But,neitherstaticimagesnortimelapseanalysishaverevealedanincreaseincellproliferationintheepitheliumatbranchsitesbeforebrancheshaveformed.Thissuggeststhatconceptualandcomputationalmodelsthatrelysolelyongrowthfactor-inducedproliferationtogenerateanepithelialbranchneedtobereconsidered.Furthermore,severalquestionsstillremainunanswered.Forexample,allexamplesofbranchingmorphogenesisexaminedthusfarrequirethepresenceofoneormoregrowthfactors(e.g.FGF,VEGF,EGF),buthowdoesthedevelopingepitheliumdistinguishbetweenthecapacityofthesemoleculestoactasmitogens,andthecapacitytoinduceabranch?Furthermore,oncethebranchhasformed,whyisproliferationuniversallyincreasedinthecellsatthetipofthebranch?Whatadditionalsignalsareneededforthispatterning?Timelapseimageanalysisoftissue-specificreportermicemayyieldsomecluestoanswerthesequestions.MolecularhomologydoesnotequalmechanistichomologyDespitethefactthatmanyofthesamesignalingmoleculesareusedduringbranchingmorphogenesisoftheDrosophilatracheaandvertebratelung,thephysicalmechanismsthatgeneratebranchesaredistinct.Bnl(FGF)inducesasproutingmorphogenesisprocessinthetracheaofthefly,andcanclearlybeconsideredasachemoattractant,oratleastamotogen,inthissystem.Bycontrast,FGFinducesapicalconstrictionandfoldingoftheairwayepitheliumintheembryonicchickenlung,whereasitrepressesepithelialdifferentiationintheembryonicmouselung(Volckaertetal.,2013).ThereisnoevidencetosuggestthatFGFactsaseitheraclassicalchemoattractantorasamotogeninthelungsofbirdsormammals.Giventhismajordistinction,futureinvestigationsmaywishtoavoiddrawingtoomanyconclusionsbasedonmolecularhomologyalone.Ofcourse,thisbegsthequestion:howdohomologoussignalingpathwaysyieldsuchadiversityofphysicalmechanisms?Havethedownstreammoleculardetailschangedoverthecourseofevolution?Or,isthemolecularhomologysimplymisleadingoursearchforblueprintsthatgovernthedevelopmentofbranchingepithelia?Thesequestionsarenotlimitedtobranchingsystems.Forexample,similarinstancesofmolecularsimilaritydespitephysicaldissimilarityhavebeenobservedinthevertebrateheart.Manyofthetranscriptionfactorsinvolvedinearlycardiogenesis,includingNkx2.5andGata5,areconservedacrossspecies,butthetissuedeformationsthatdriveheartdevelopmentcanbeverydifferent,asdemonstratedbythemajordifferencesincardiogenesisbetweenfishandbirds.ThereisnoparadigmaticbranchingepitheliumAlthoughcomparisonscanbemadebetweenorgansystems,thedifferencesbetweenthemarelargeenoughtosuggestthatnosinglebranchingepitheliumcanbeconsideredasrepresentativeofthe 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developmentofallbranchingsystems.Assuch,wesuggestthatincreasedattentionshouldbegiventotheprecisionofthelanguageusedtodescribebranchingmorphogenesis.Forexample,despitethefactthatmanybranchingepithelialackobviousmembraneprotrusions,morphogenesisoftheseorgansisoftendescribedasaninvasiveprocess,withoutclarification.PerhapsthisisarelicofthecomparisonsbetweenlungbranchinginmiceandtrachealdevelopmentinDrosophila.Nonetheless,imprecisedescriptionsmayhinderprogressinthisfieldifinaccurateorinappropriatephysicalmechanismsareerrantlyassociatedwithbranching.Again,thisrealizationpromptsadditionalquestions.Whyaredistinctphysicalmechanismsusedtocreateverysimilarepithelialarchitectures?Whydothesameorgansindifferentspeciesdevelopusingverydifferentphysicalmechanisms?Howmanydifferentbranchingmorphogeneseshavebeenrealizedoverthecourseofevolution?Increasedattentiononquantitativeanalysisandnewmodelsystemswilllikelyshedlightonthese,andother,unansweredquestions.CompetinginterestsTheauthorsdeclarenocompetingfinancialinterests.FundingWorkintheauthorsgroupwassupportedinpartbygrantsfromtheNationalInstitutesofHealth,bytheDavid&LucilePackardFoundation,bytheAlfredP.SloanFoundationandbytheHenry&CamilleDreyfusFoundation.C.M.N.holdsaCareerAwardattheScientificInterfacefromtheBurroughsWellcomeFund.DepositedinPMCforreleaseafter12months.ReferencesAffolter,M.andCaussinus,E.(2008).TrachealbranchingmorphogenesisinDrosophila:newinsightsintocellbehaviourandorganarchitecture.Development,2055-2064.Alcaraz,J.,Mori,H.,Ghajar,C.M.,Brownfield,D.,Galgoczy,R.andBissell,M.J.(2011).Collectiveepithelialcellinvasionovercomesmechanicalbarriersofcollagenousextracellularmatrixbyanarrowtube-likegeometryandMMP14-dependentlocalsoftening.Integr.Biol.(Camb.),1153-1166.Alescio,T.andCassini,A.(1962).Inductioninvitrooftrachealbudsbypulmonarymesenchymegraftedontrachealepithelium.J.Exp.Zool.,83-94.Alescio,T.andColomboPiperno,E.(1967).Aquantitativeassessmentofmesenchymalcontributiontoepithelialgrowthrateinmouseembryoniclungdevelopinginvitro.J.Embryol.Exp.Morphol.,213-227.Alescio,T.andDiMichele,M.(1968).Relationshipofepithelialgrowthtomitoticrateinmouseembryoniclungdevelopinginvitro.J.Embryol.Exp.Morphol.227-237.Arthur,W.T.,Petch,L.A.andBurridge,K.(2000).IntegrinengagementsuppressesRhoAactivityviaac-Src-dependentmechanism.Curr.Biol.,719-722.Auerbach,R.(1960).Morphogeneticinteractionsinthedevelopmentofthemousethymusgland.Dev.Biol.,271-284.Bellusci,S.,Grindley,J.,Emoto,H.,Itoh,N.andHogan,B.L.(1997).Fibroblastgrowthfactor10(FGF10)andbranchingmorphogenesisintheembryonicmouseDevelopment,4867-4878.Bentley,K.,Mariggi,G.,Gerhardt,H.andBates,P.A.(2009).Tippingthebalance:robustnessoftipcellselection,migrationandfusioninangiogenesis.PLoSComput.Biol.,e1000549.Bernfield,M.andBanerjee,S.D.(1982).Theturnoverofbasallaminaglycosaminoglycancorrelateswithepithelialmorphogenesis.Dev.Biol.,291-305.Bernfield,M.R.,Banerjee,S.D.andCohn,R.H.(1972).Dependenceofsalivaryepithelialmorphologyandbranchingmorphogenesisuponacidmucopolysaccharide-protein(proteoglycan)attheepithelialsurface.J.CellBiol.,674-689.Bernfield,M.R.,Cohn,R.H.andBanerjee,S.D.(1973).GlycosaminoglycansandEpithelialOrganFormation.Am.Zool.,1067-1083.Biyashev,D.,Veliceasa,D.,Topczewski,J.,Topczewska,J.M.,Mizgirev,I.,Vinokour,E.,Reddi,A.L.,Licht,J.D.,Revskoy,S.Y.andVolpert,O.V.miR-27bcontrolsvenousspecificationandtipcellfate.,2679-2687.Borghese,E.(1950).ThedevelopmentinvitroofthesubmandibularandsublingualglandsofMusmusculus.J.Anat.,287-302.Bresciani,F.(1968).TopographyofDNAsynthesisinthemammaryglandoftheC3Hmouseanditscontrolbyovarianhormones:anautoradiographicstudy.CellTissueKinet.,51-63.Brownfield,D.G.,Venugopalan,G.,Lo,A.,Mori,H.,Tanner,K.,Fletcher,D.A.andBissell,M.J.(2013).Patternedcollagenfibersorientbranchingmammaryepitheliumthroughdistinctsignalingmodules.Curr.Biol.,703-709.Cardoso,W.V.,Itoh,A.,Nogawa,H.,Mason,I.andBrody,J.S.(1997).FGF-1andFGF-7inducedistinctpatternsofgrowthanddifferentiationinembryoniclungepithelium.Dev.Dyn.,398-405.Casanova,J.(2007).Theemergenceofshape:notionsfromthestudyoftheDrosophilatrachealsystem.EMBORep.,335-339.Caussinus,E.,Colombelli,J.andAffolter,M.(2008).Tip-cellmigrationcontrolsstalk-cellintercalationduringDrosophilatrachealtubeelongation.Curr.Biol.Chi,X.,Michos,O.,Shakya,R.,Riccio,P.,Enomoto,H.,Licht,J.D.,Asai,N.,Takahashi,M.,Ohgami,N.,Kato,M.etal.(2009).Ret-dependentcellrearrangementsintheWolffianductepitheliuminitiateuretericbudmorphogenesis.Dev.Cell,199-209.Chu,J.Y.S.,Sims-Lucas,S.,Bushnell,D.S.,Bodnar,A.J.,Kreidberg,J.A.andHo,J.(2014).Dicerfunctionisrequiredinthemetanephricmesenchymeforearlykidneydevelopment.Am.J.Physiol.RenalPhysiol.,F764-F772.Daley,W.P.,Gulfo,K.M.,Sequeira,S.J.andLarsen,M.(2009).Identificationofamechanochemicalcheckpointandnegativefeedbackloopregulatingbranchingmorphogenesis.Dev.Biol.,169-182.Daley,W.P.,Kohn,J.M.andLarsen,M.(2011).Afocaladhesionprotein-basedmechanochemicalcheckpointregulatescleftprogressionduringbranchingmorphogenesis.Dev.Dyn.,2069-2083.Davies,J.A.(2002).Dodifferentbra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