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Bio127 SectionI
IntroductiontoDevelopmentalBiology
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CellCellCommunicationinDevelopment
Gilbert9e Chapter3
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IthastobeEXTREMELYwellcoordinatedforthe ___________________________________
singlecelledfertilizedovumtodevelopintothe
complexadult
Thiscoordinationrequiresasystematicwayforthe ___________________________________
cellstoknowwhatshappeningaroundthemsothat
theycanchangetheirgeneexpressioncorrectly
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Theymustalsothenchangethesignalstheyare
sendingouttoletsurroundingcellsknowwhat
changestheyaremaking ___________________________________

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DevelopmentalActivitiesCoordinatedinthisWay ___________________________________

1.Theformationoftissuesfromamixofindividualcells ___________________________________
2.Theformationoforgansfromamixoftissuetypes
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3.Theformationofcells,tissuesandorgansinspecificlocations

4.Thegrowthanddeathofcells,tissuesandorgans
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5.Theachievementofpolarityincells,tissueandorgans ___________________________________

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 ___________________________________

Theplasmamembranesofcellsaredesignedto ___________________________________
sensewhatishappeningintheirenvironment

Membranemoleculessense: ___________________________________
othercellmembranes
solublesignalssentbyothercells
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thetypeofextracellularmatrixthatsurroundsthem

Afewsignalscangetpasttheplasmamembrane ___________________________________

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Mostcellsintheembryohavemolecules ___________________________________
ontheirsurfacethatidentifywhotheyare
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Thesemoleculesalsoinstructthem
whotheyshouldbeincontactwith

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Sortingoutandreconstructionofspatialrelationships ___________________________________
inaggregatesofembryonicamphibiancells
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All ___________________________________
cell
types
can ___________________________________
doit

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 Aggregatesformedbymixing7daychickembryo ___________________________________
neuralretinacellswithpigmentedretinacells
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....justtoshow
thatitsmore
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thananartists
rendition....
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Figure3.4Hierarchyofcellsortinginorderof
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decreasingsurfacetensions
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Themore ___________________________________
adhesivethe
cellsplasma
membraneis, ___________________________________
themoreit
migratesto
themiddleof
acellmixture.
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Themolecularbiologyofcelladhesion:Cadherins ___________________________________

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Thecalciumdependent Themoreyouexpress,
adhesionmolecules themorecentralyou
(orcadherins)arethe becomeinamixture ___________________________________
mainsourceofadhesive
activityonthecellsurface
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 ___________________________________
Importanceofamountofcadherin formorphogenesis
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Anearlyperfectlinearrelationship

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Importanceoftypeofcadherin formorphogenesis ___________________________________

EarlyembryocellsallexpressEcadherin
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PresumptiveneuraltubecellsloseEcadherin andgainNcadherin.
Ncadherin expressiondoessomethingverysimilarinlimbcartilage.
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Cadherins canactivatemigrationthroughactin

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Cadherin bindingoutsideof
thecellcancauseactinbased
migrationinsomecells ___________________________________

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DisruptionofNCadherin inFrogEmbryos ___________________________________

failedmigration failedactin assembly ___________________________________

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blocked normal

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Thecadherins activatemigrationthroughRhoGTPase ___________________________________

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MigratorycellshaveRho
intheircadherinactin
apparatus cadherin
activatesRho,Rhoactivates
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actinmyosinmigration.

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Drosophila gastrulation ___________________________________

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ThecellsthathaveRhoactivated
migratetobecomethemesoderm.
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 MigrationisstartedbyexpressionofTwistandSnail ___________________________________
whichcausesRhoandBcatenin totranslocate incells

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RhobuilduponEcadcausesactin polymerizationandmigration
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TrachealDevelopmentinDrosophila ___________________________________

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Rhocanalsobelinkedtocell ___________________________________
surfacereceptorsandcause
chemotactic migration.
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Thecadherin attachments
remainstrongandthecells
migrateasacohesiveunit.
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Mesenchymal CellMigrationisalsoRhoDependent
Figure3.12Cellmigration
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notalwayscadherindependenthowever! ___________________________________

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 ___________________________________
OneWay,TwoWayandReciprocal
CommunicationsStrategies
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Ligands
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Receptors
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2nd Messengers
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TargetMechanisms
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CellSignalingTerminology
Paracrine ___________________________________
Endocrine
Synaptic
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Induction
Inducer
Responder ___________________________________
SignalCompetence
SignalTransduction ___________________________________
PermissiveSignals
InstructiveSignals ___________________________________

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Ectodermal competenceandtheabilitytorespondto ___________________________________

theopticvesicleinducerinXenopus
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 ___________________________________
HOW?
Opticvesiclesecretes......
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BMP4
Fgf 8
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Headectodermexpresses......
Sox2
LMaf ___________________________________
Pax 6

Lensgenesturnedon...... ___________________________________
crystallin
others ___________________________________

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INDUCED DIFFERENTIATION ___________________________________

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InductionCascades
Weknowthattissuestendtoaggregatethroughcell ___________________________________
contact

Itscommonfortissuestoplayoffeachotherto ___________________________________
produceanorgan

Anythingfromtwotissuessignalingbackandforthto
manytissuescoordinatingeachothersactions
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Thecommonthemeisthatachangeingene
expressioninternally(TFs,functionalproteins)is ___________________________________
oftenaccompaniedbyachangeinsecretedproteins
(paracrine,endocrinefactors)
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 ___________________________________
Eyeformationisaclassicallystudiedcascadeofinduction

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Simplelensinduction... ___________________________________

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RECIPROCAL INDUCTION
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Thereciprocalinteractionbetweenan ___________________________________
epitheliumandacloselyassociated
mesenchyme isaverycommonmeans ___________________________________
oforgandevelopment(organogenesis)
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Theseare
backwards ___________________________________

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 Differentmesenchyme inducesdifferent ___________________________________
epithelialstructures
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Also,differentepitheliumcanonlybecome ___________________________________
whattheyarecompetenttobecome
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Alittleaboutsomeoftheactualmolecules.....
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GrowthFactorscarrymostofthesignals
Hormonesandneurotransmitterslateron
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4bigfamilies:
FGF,Hedgehog,Wnt,TGF
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Receptorsandsignalingcascadespremadefor
themmakeyoucompetent ___________________________________

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 ___________________________________

Fibroblastgrowthfactor(FGF)familyare ___________________________________
classicgrowthfactors:FGF18
lotsofothers:VEGF,HGF,PDGF,etc.
canchangetranscriptionofgenes2ways
___________________________________
RTKPathway:receptortyrosinekinase
JAKSTAT:JAKactivatesSTATTFs ___________________________________

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Opticvesiclesecretes......
BMP4 ___________________________________
Fgf8

Headectodermexpresses...... ___________________________________
Sox2
LMaf ___________________________________
Pax6

Lensgenesturnedon...... ___________________________________
crystallin
others
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Figure3.20Fgf8inthedevelopingchick(Part1) ___________________________________

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 ___________________________________
Figure3.20Fgf8inthedevelopingchick(Part2)
FGF8inopticvesicle LMaf expressioninectoderm
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Figure3.24AmutationinthegeneforFgfR3causesthe ___________________________________
prematureconstitutiveactivationoftheSTATpathwayand
theproductionofphosphorylated Stat1protein
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Hedgehogfamilyincludessonic(shh),desert ___________________________________
(dhh)and indian (ihh) invertebrates
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Changetranscriptionthroughaninteresting
seriesofinhibitoryactivities
thepatched receptorinhibitsthesmoothened ___________________________________
proteinuntilhedgehog binds
smoothened thenmovestoinhibitproteinsthat
inhibittheGli activatorprotein ___________________________________

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Figure3.26(A)Sonichedgehogexpressionisshownbyinsitu ___________________________________
hybridizationinthenervoussystem,gut,andlimbbudofa
chickembryo.(B)Headofacyclopic lamb
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Bothshh andpatched proteinsrequirecholesterol.
Blockingitsproductioncancausecyclopism.

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Wnt familyhas15membersinvertebrates
Glycoproteins withlipidtails!
Workthroughfrizzled receptorsanddisheveled
___________________________________
activators(flyguys!)
Alsoactivatebyinhibitionofaninhibitor ___________________________________

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Interestingly,Wntcandomuchofwhat ___________________________________
cadherinscando
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Sendcatenins tothenucleus

Activaterho andchangethecytoskeleton
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Thisiscalledcrosstalkanditisveryimportantin ___________________________________
cellsignaling

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 Rememberthestructureofthecadherinsystem ___________________________________
Implantationofthemammalianembryoinadhereto
theuterinewall ___________________________________
E andPcadherin
IntegrinanduterineECM
Proteinsthatbindsugarsonuterinewall Rhoproteins
___________________________________
associatewith
cateninsand
actinsystem.
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Theycanchange
actinsstructure.

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TheTGF superfamily isaverylargefamilyof ___________________________________

veryactivepeptidegrowthfactors
involvedinthedevelopmentofmosttissues
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Thereceptorsarealsoalargefamilyof
proteins
___________________________________
Theyareserinethreonine kinases,notRTK

TheyworkthroughtheactivationofSMAD ___________________________________
transcriptionfactors

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Figure3.29Relationshipsamongmembers
oftheTGFsuperfamily
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Wellhearalot ___________________________________
ofthesenames
againthissemester!

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 ___________________________________

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Remember:

TheBig4arejustpartofthestory
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Welltalkaboutothersastheycomeintoplay ___________________________________

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TheDeltaNotchfamily:Juxtacrinesignals ___________________________________
Transmembrane proteinsoncellsincontact
Delta,JaggedorSerratebindtoNotchfamily ___________________________________
Signalsgobothways

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TheNotchsignalisinterestinginthatitsinternal
domainiscleavedandentersnucleus
Thisactivatesadormanttranscriptionfactor ___________________________________

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Figure3.33MechanismofNotchactivity
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 ___________________________________
Apoptosis:geneticallyprogrammedcelldeath

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Absolutelyessentialtocontrolcellnumbers,
cellqualityandtocreatespace
Thespacebetweenourfingers
___________________________________
2/3ofallneuronswemake
Themiddleear ___________________________________
Thecerebralventricles
Frogtails ___________________________________
Malemammaryepithelium

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Figure3.32Disruptionofnormalbrain ___________________________________
developmentbyblockingapoptosis
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Apoptosis
Oftencellsaresettoapoptose bydefault ___________________________________

Theyrequireasignaltokeepthemalive ___________________________________
Thesignalcanbesolubleorcanbeattachment,such
ascadherins,integrins ___________________________________

Theseareguaranteesthatcellsremainwherethey ___________________________________
shouldbeinthebody

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 ___________________________________
Figure3.31Apoptosispathwaysinnematodes
andmammals
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Earlywork Mammalian
donemostly homologs
inworms ___________________________________

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Asignalthat
turnsonCED9
(Bcl2)savesthe
cellfromdeath ___________________________________

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Other Related Strategies
of Developmental Biology
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A. Maintaining the differentiated state ___________________________________

B. The extracellular matrix as a source of
developmental signals ___________________________________
C. Epithelial-mesenchymal transition
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MaintainingtheDifferentiatedState
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Justchanginggeneexpressionisnotenough

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Maintainingthenewexpressionpatternisessential
fordifferentiation
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Sofar,fourwaystodothishavebeendescribed

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 Fourwaysofmaintainingdifferentiationafter ___________________________________
theinitialsignalhasbeengiven(Part1)
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TFPositivefeedbackloop Trithorax openspromoter

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Fourwaysofmaintainingdifferentiationafter
theinitialsignalhasbeengiven(Part2)
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Autocrine loop Paracrine loop

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TheRoleoftheExtracellularMatrix(ECM)
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Asdevelopmentproceeds,allcellssecrete
sugarsandproteinstocreatesolidsubstrate
betweenthecells ___________________________________

Nearlyallcellsrequireadhesiontosurvive ___________________________________

CellmigrationisalsodependentonECM ___________________________________

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 Figure3.37Extracellularmatricesinthe ___________________________________
developingembryo
Afibronectin tractallowsmesodermmigrationduringgastrulation
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Theepithelialcellssecrete
fibronectin intobasallamina
andthencanuseitmigrateupon.
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Figure3.38Simplifieddiagramofthe
fibronectin receptorcomplex
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IntegrinsbindtheECM
tothecytoskeleton

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Figure3.40Basementmembranedirected ___________________________________
geneexpressioninmammaryglandtissue
Platedonplastic
___________________________________
(A)

Platedon
basallamina
___________________________________
(B,C,D)

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 EpithelialtoMesenchymal Transition ___________________________________

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Akeytypeofdifferentiationinmanytissue
formingactivitiesinembryosandadults
formationofmesodermfromepiblast ___________________________________
formationofneuralcrestcellsfromneuraltube
formationofcoronaryarteriesfromepicardium
formationofvertebraefromsomites
___________________________________
woundhealinginskinandvasculature
metastasisofepithelialcancers ___________________________________

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Figure3.41Epithelialmesenchymal
transition,orEMT(Part1)
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Ifnotaccompanied
bydifferentiation,
lossofconnections ___________________________________
wouldleadtodeath

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Figure3.41Epithelialmesenchymal
transition,orEMT(Part2)
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