05 02-07 Early Brain Development

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EarlyBrainDevelopmentSpring2013

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MedicalNeuroscience|TutorialEarlyBrainDevelopment

MAPTONEUROSCIENCECORECONCEPTS1

NCC2. Neuronscommunicateusingbothelectricalandchemicalsignals.

NCC3. Geneticallydeterminedcircuitsarethefoundationofthenervoussystem.

NCC4. Lifeexperienceschangethenervoussystem.

LEARNINGOBJECTIVES

Afterstudyoftheassignedlearningmaterials,thestudentwill:

1. Characterizetheeventsthatoccurduringgastrulationandneurulation.2. StatethesignificanceofinductionfortheinitialdevelopmentoftheCNS.3. Discussthefactorstheguidemigratingneuroblaststotheirfinaldestinationsinthedeveloping

graymatterstructuresoftheCNS

4. CharacterizethecellularmechanismsthatinfluencethedifferentiationofneuronsandgliaintheCNS.

5. DescribetheroleofapoptosisinCNSdevelopment.

TUTORIALOUTLINE

I. IntroductionA. mechanismsofneuraldevelopment

1. geneticspecification: lineage-derivedsignalsexpressedviagenetranscription2. self-organization: cell-cellinteractionsmediatedviamolecularandactivity

basedmechanisms

3. sensorimotorexperience:environmentalinteractionsexpressedlaterinneuraldevelopment(oncesensoryandmotorsystemsbecomefunctional)and

throughoutlife

B. eachofthesebasicmechanismsissubjecttomodificationduetotheconsequencesofgeneticmutation,disease,exposuretoenvironmentalanddietarytoxins,ornormaland

abnormaluse(sensorimotorexperience)

1 VisitBrainFacts.orgforNeuroscienceCoreConcepts (2012SocietyforNeuroscience)thatofferfundamentalprinciples

aboutthebrainandnervoussystem,themostcomplexlivingstructureknownintheuniverse.


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1. mostmajorcongenitalmalformationsoftheCNSoccurasaresultofdysfunctionintheexpressionofgeneticspecificationorthecell-cellinteractionsthatgive

risetoorderedpatternsofstructureandconnectivityinneuralcircuits

2. inlaterstagesofbraindevelopment,sensorimotorexperienceshouldbe

consideredanimportantfactorinneurologicalfunction/dysfunction

II. InitialFormationoftheCNSA. Gastrulation

1. invaginationofthedevelopingblastulathatproducesthreegermlayers:a. ectoderm(outerlayer):givesrisetotheentirenervoussystem!b. mesoderm(middlelayer):formsmuscle,skeleton,connectivetissue,

cardiovascularandurogenitalsystems

c. endoderm(innerlayer):formsgutandassociatedviscera2. formsthenotochordalongthedorsalmidlineoftheembryofrommesoderm;

thistransientstructuredefinesthemidline,theplaneofbilateralsymmetry,and

theprincipleaxesoftheembryo(anterior-posterior;dorsal-ventral;medial-

lateral)

B. Neurulation(3-4weeksofgestation)1. formationoftheneuralplateanditssubsequentfoldinguponitselftoformthe

neuraltube(Figure22.12)

a. thenotochordgivesrisetochemicalsignalsthatinducethedifferentiationofneuralprecursorcellsintheoverlyingectoderm

b. thisspecialpartoftheectodermbecomesadistinctcolumnarepitheliumcalledtheneuralplate

2. thelateralmarginsoftheneuralplatefoldinwardandthensealofftoformtheneuraltube

a.

theneuraltubedifferentiatesintotheentireCNSi. allcellularcomponentsoftheCNSarederivedfromthe

epitheliumoftheneuraltube

ii. thelumenoftheneuraltubebecomestheventricularspacesofthematurebrainandspinalcord

2FigurereferencestoPurvesetal.,Neuroscience,5

thEd.,SinauerAssoc.,Inc.,2012.[clickhere]

Induction:Theabilityofacellortissuetoinfluencethefateofnearbycellsduringdevelopmentbythesynthesisandsecretionofchemicalsignals(peptidehormones)thatmodulategeneexpression.Thespecificityandprecisetimingofinductivesignalingiscrucialfornormaldevelopment.


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b. thenotochordcontinuestoprovideaninductiveinfluenceastheventralportionofneuraltubedifferentiatesintothefloorplate(seeFigure

22.2)

i. inturn,inductivesignalsarisefromthefloorplateandinfluencethedifferentiationofneuralprecursorcellsintheventralparts

oftheneuraltube

ii. somecellsintheseregionseventuallybecomethemotorneuronsandinterneuronsofthebrainstemandspinalcord

c. attheothersideoftheneuraltube,dorsalneuralprecursorcellsareinducedtoformthe roofplate,whichinturninducestheformationof

sensorysystemneuronsofthebrainstemandspinalcord

d. athirdspecialregionoftheneuraltube,alsoalongthedorsalmidline,differentiatesintotheneuralcrest(seeFigure22.2)

i. neuralcrestcellsmigrateawayfromtheneuraltubeii. alongtheway,theyareinfluencedbyabroadspectrumofchemicalsignalsthatdeterminetheirmigratoryfateand

ultimateidentify

iii. neuralcrestprogenygiverisetoalltheneuronsandgliaoftheperipheralnervoussystem,theneurosecretorycellsofthe

adrenalmedulla,theneuronsthatconstitutetheenteric

nervoussystem,andothernon-neuralcells( seeFigure22.11)

e. severalcongenitalmalformationsoftheCNSresultfromafailureoftheneuraltubetocompleteseal(e.g.,spinabifida,anencephaly)

III.

FormationofMajorSubdivisionsoftheCNS(3-4monthsofgestation)A. morphologicalalterationsoftheneuraltube( seeFigure22.3)

1. rapidanddisproportionatecellularproliferationtogetherwithmovementsthatbend,foldandconstrictdifferentpartsoftheneuraltubegiverisetothemajor

subdivisionsoftheembryonicbrain

2. aftertheinitialformationofthemajorsubdivisionsoftheembryonicCNS,additionalpartitioningoftheprosencephalonestablishestheearly

telencephalon,diencephalonandtheopticcups,whichgiverisetotheretina

3. similarly,therhombencephalonpartitionsintothemetencephalon(cerebellumandpons)andthemyelencephalon(medullaoblongata)

reviewtherelationbetweenstructuresintheadultbrainandtheirembryological

origins;seeTableA24

4. theseregionalchangesthatshapethedevelopingneuraltubeareinfluencedbythespatialandtemporalexpressionpatternsof homeoticgenes

a. infruitflies,homeoticgenesencodeDNA-bindingproteinsthatguidethedifferentiationoftheembryointodistinctsegments,definingthe

anterior-posterioraxisofthebodyplan( seeFigure22.4)


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b. similargenes,calledHoxgenes,havebeenfoundinmammals,includinghumans

c. likehomeoticgenes,HoxgenesencodeDNA-bindingproteinsthatmodulatetheexpressionpatternsofothergenes;theseproteinsare

importantmediatorsofneuralinduction

i. inhumans,wehavefourclustersofHoxgenes,witheachonadifferentchromosome

ii. theirexpressioncontributestothecellularandmolecularprocessesthateventuallyproducedifferentiatedregionsalong

theanterior-posterioraxisofthedevelopingneuraltube( see

Box22B)

B. molecularbasisofneuralinduction1. molecularinteractionsbetweencells(inearlyembryogenesis,betweencellsin

adjacentgermlayers)thatareessentialforshapingregionalandcellularidentity

(seeFigure22.5A)

a. inductivesignalsaresecretedby:notochord,floorplate,roofplate,somites,specificfociwithintheneuroectoderm(tonameafewsources)

b. inductivesignalsaresecretedanddiffusethroughextracellularspacestoactonadjacenttissues

2. examples:a. steroidhormones:retinoicacid(RA)(seeFigure22.5B)

i. small,lipophilicmoleculederivedfromvitaminAii. activatesretinoidreceptors,whicharetranscriptionfactorsthat

modulatetheexpressionoftargetgenesiii. RAsignalingdrivescellulardifferentiation,regulatingtransitions

betweenclassesofneuralstemcells

iv. excessorinsufficientvitaminA(orretinoid-basedmedications)candisruptearlybrainmorphogenesis(seeBox22C)

b. peptidehormones:fibroblastgrowthfactor,bonemorphogeneticproteins,Wnthormonefamily,andsonichedgehog

i. bonemorphogeneticproteins(BMPs)( seeFigure22.5D)- BMPsaresecretedbysomitesandsurroundingmesodermal

tissues

- andbindtoreceptorserinekinasesthatphosphorylatetranscriptionalregulators(SMADs),whichinturn

translocatetothenucleusandmodulategeneexpression

- inducetheformationofbonecellsinmesoderm(hencetheirname);butalsotheyinduceepidermis(skin)in

ectodermaltissue


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- unlesstheyareantagonized(byNogginandChordin),whichthenallowstheectodermtodifferentiateinto

neuroectoderm

- evidently,theCNSisrescuedfrombecomingskinbyantagonizingBMPactivity!

ii. sonichedgehog(Shh)(seeFigure22.5G)- importantforneuraltubeclosure- importantforestablishingidentity- whenpresent,itbindstosurfacereceptorsandpromotesa

switchfromtranscriptionrepressorstotranscription

activators(Gli1-3)thatmodulategeneexpression

3. inductivesignalingprovidesatranscriptionalcodeforestablishinglocalidentityinspecificregionsofthedevelopingCNS,includingtheforebrain( see

Figure22.6C-D)

C. generationanddifferentiationofneuronsandglia1. intheadultbrain,thereareabout 100billionneurons(andevenmoreneuroglial

cells)!

2. duringthepeakcellproliferation,therateofneurogenesisisnearly 250,000neuronsperminute!

3. nearlyallneuronsaregeneratedbythemiddleofthesecondtrimester;thereafter,onlyveryfewneuronsareevergeneratedintheCNS!(considerthe

implicationsforlearningandmemory,motorskillacquisition,neuropathology

andneuralrehabilitation)

4.

neuronalandglialgenesisoccursintheventricularzone a. precursorcellsdivideintheventricularzoneandproduceotherstem

cellsformany(symmetrical)mitoticcycles(seeFigure22.7)

b. afterasymmetricaldivision,oneofthetwodaughtercellsisdestinedtodifferentiateintoaglialprecursorsandothersintoneuronalprecursors,

calledneuroblasts(seeFigure22.10)

c. postmitoticneuroblastsmigrateawayfromtheventricularzonetowardatargetstructure,suchasthedevelopingcerebralcortex,calledthe

corticalplate ,orremainclosertotheventricularzonetopopulate

subcorticalgraymatter(primordialbasalgangliaanddiencephalon)

i. manyneuronsintheCNSareguidedtofinaldestinationsby(presumptive)glialcellsthatspanthedistancebetweenthe

ventricularzoneandthepiamater

- forthedevelopingcorticalplate,neuroblastsmigratealongradialglialcells (seeFigure22.12-13)


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- whenneuroblastsreachtheirfinaldestination,theydissociatefromradialglialprocessesandtakeup

residenceinaparticularlaminarorspatialposition

- inthecorticalplate,neuroblaststhatwillcometopopulatethedeeperlayersaregeneratedfirstand

migratetotheinnermostlaminae( seeFigure22.8)

- later,moresuperficialneuroblastsaregeneratedandmigratethroughthedeeperlayerstoreachtheouter

laminaeofthedevelopingcorticalplate

- thecorticalplatedevelopsinaninside-outpattern- thus,organizedperiodsofneurogenesisareimportant

forthedevelopmentofregion-specificcelltypesand

axonalconnections

ii. anumberofcongenitalmalformationsaretheresultofmigrationerrors;eventsubtleerrorsmayleadtoformsof

mentalretardationandcerebralpalsy

iii. neuroblaststhatdifferentiateintoinhibitoryinterneuronsarederivedfromthedeepganglioniceminenceandmigrate

tangentiallytoreachtheirfinaldestinations( seeBox22F)

D. howdoprecursorcellsdifferentiatetoproducethediverseformsofneuronsandgliathatarepresentinthematureCNS?

1. localcell-cellinteractionsmediatedbycellsurfacereceptors(whoacellsneighborsare),manyofwhicharethosesamesignalsthatservedinductive

signalingatsomeearlierstageindevelopment( seeFigure22.10)

2. celllineagedistincthistoriesoftranscriptionalregulation(whoacellsparentis)E. aftertakingupresidenceinatargetstructure,asignificantportionoftheneurons

produced(roughlyhalfincertainCNSregions)undergo apoptosis

1. programmedcelldeathrequiringtheexpressionofso-calledsuicidegeneswhoseproductspromotethedysfunctionanddissolutionofotherwiseviable

cells

2. cellsthatundergoapoptosisarenotnecessarilylessfit(thisdoesnotseemtobeaDarwinian-likedevelopmentalprocess)

F. inthethirdtrimesterandinearlypostnatallife,theneuronsthatsurviveelaboratedendriticarborsandsendoutaxons(thestorycontinuesinthenextfewtutorials)


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STUDYQUESTIONS

Q1. WhichofthefollowingstatementsaboutthenotochordisMOSTaccurate?

A. Thenotochordisderivedfromtheectodermalgermlayer.B. Formationofthenotochordistheprincipaldevelopmentalachieveofneurulation.C. Thenotochordprovidesamigratorypathwayforneuralcrestderivativesasthey

migratetowardtheirfinallocationsinthedevelopingembryo.

D. Thenotochordisanimportantsourceofinductivesignalsthatinducetheformationoftheneuralplateintheoverlyingectoderm.

E. Thespinalcordofthematurethenervoussystemisderivedfromthecellsoftheembryonicnotochord.

Q2. Whatfactororfactorsaccountforthegenerationofdiversityamongtheprogenyof

neuroblasts?

A. localcell-cellinteractionsmediatedbycellsurfacereceptorsB.

thedistincthistoriesoftranscriptionalregulationintheprogenyC. bothcell-cellinteractionsandtranscriptionalhistorycontributetocellulardiversityinthedevelopingCNS

05 02-07 Early Brain Development

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