EMBRYOLOGY

AboutEmbryologyandthisguide: ThisguideiswrittenfromDr.Hillsnotes.AlloriginalworkisthatofDr.Hill.Thesehavebeenwrittenin narrativeformandhavesomeminorcommentaryinsertedontopofDr.Hillsinformation.Thisguide (andDr.Hill)requiresaworkingknowledgeofAnatomyandAnatomicalvocabulary(especially direction).Youwillbechallengedtokeepupinlecture,lessyouprepareaheadoftime.ItisNOTthatDr. Hillisapoorteacher,orhislecturespoorlydesigned.Rather,Embryologyhasavocabularyallitsown, oneDr.Hillisfluentin,andoneyouhavenotseen.HeiscorrecttotheT,whichcansometimesbe difficulttofollow. Dr.Hilllovesdetail.Hisquestionsarenitpickyanddetailed.Theyarehardlyeverconceptualandare oftentakenasasinglelinefromhisnotes.Thereisnowayoftellingexactlywhathewantsyoutoknow, butknowthis:DRHILLWILLNEVERASKYOUANYTHINGHEHASNOTTAUGHTYOUINLECTURE.That beingthecase,unlessyoureallylikeembryo,Mooresembryobookismostlyuseless.Itcanhelpyou understandwhatsgoingon,buthassomuchsuperfluousdetail. Someofthelecturesforthisyearwerepresentedlastyear,butdidnotcomewithhandoutstodevelop forthisguide.Thoselecturesmarkedas(Ghost) inthetableofcontentshavenocontent.Ratherthan writinganerroneousguidethatmaymisleadyou,IleaveituptoyourNoteServiceandlecture recordingstofillintheblanks.Rememberthatinpurchasingthisguideyouarealreadyenrolledinthe AnatomyTrimesterofNoteService. Inthetruespiritofthisguide: TakeAway:Embryoistoughtokeeppacewithinlecture,Dr.HilliscorrecttotheTandwillonlyaskyou whatheteachesyou,andsomeofthisguidewillhavetobefilledinbyyouryear. Sincerely, TheAuthor

EMBRYO
Date Aug 5 Aug 6 Aug 7 Aug 11 Aug 18 Class Page IntroductiontoEmbryologyGametogenesisandMeiosis 1 Fertilzation,Preimplantation,BilaminaryEmbryo 5 TrilaminarEmbryo 12 DevelopmentofSpineandPNS16 DevelopmentofMusculoskeletalSystem 19

EmbryoAugust5thIntroductiontoEmbryology

Gametogenesis Meiosistheprocessinwhichadiploidcellbecomesmultiplehaploidcellsbyundergoingtwosubsequent divisionswithoutsequesteringandthechancetoreduplicatethegeneticmaterial. Spermiogenesisthelastleginthetripofspermatogenesiswherebyhaploidspermatidsaremanipulatedand turnedintospermatozoa(intheseminiferoustubules). Spermatogenesisthestepsinwhichaspermatogonia(germcell)istransformedintoaspermatozoa. Oogenesisgametogenesisforeggs PrimarySpermatocyte/Oocytediploidstageaftermitosis;readytoundergomeiosis SecondarySpermatocyte/Oocytehaploidstageaftermeiosis1. ChromatidoneoftwogeneticallyidenticalStrandsthatmakeupachromosome. Chromosomegeneticmaterialthatcodesforagene Nondisjunctiontheactioninwhichhomologouschromosomesdonotseparateduringmeiosis1orchromatids donotseparateinmeiosis2. PostZygoticNondisjunctionfailureofnormalmitosistoseparatesisterchromatids,resultinginanabnormal distributionofchromosomesequalingamosaic. MosaicifaPZNoccursduringfetaldevelopment,alldaughtercellswouldhencebedisrupted.However,all normalcellsuptothatpointwouldlikewisecontinuetodivide,sotherewouldbeamixture,amosaic,ofnormal cellsandabnormalcells,resultinginacombinationofphenotypes. PolarBodyAsymmetricalcelldivisionleadstotheproductionofpolarbodiesduringoogenesis.Toconserve nutrients,themajorityofcytoplasmissegregatedintoeitherthesecondaryoocyteorovum,duringmeiosisIor meiosisII,respectively.Theremainingdaughtercellsgeneratedfromthemeioticeventscontainrelativelylittle cytoplasmandarereferredtoaspolarbodies.Eventually,thepolarbodiesdegenerate. FIVEPHASESOFPROPHASE: (1)LeptoteneDuringthisstage,individualchromosomesbegintocondenseintolongstrandswithinthenucleus. However,thetwosisterchromatidsarestillsotightlyboundthattheyareindistinguishablefromoneanother. (2)ZygoteneOccursasthechromosomesapproximatelylineupwitheachotherintohomologouschromosomes. (3)Pachytenecontainsthechromosomalcrossover.Nonsisterchromatidsofhomologouschromosomes randomlyexchangesegmentsofgeneticinformationoverregionsofhomology (4)Diplotenethesynaptonemalcomplexdegradesandhomologouschromosomesseparatefromoneanothera little. (5)DiakinesisThisisthefirstpointinmeiosiswherethefourpartsofthetetradsareactuallyvisible. HomologousChromosomeeachpersonhastwosetsofchromosomes,onepaternalandonematernal,eachthat codeforthesamegenes.Thesearehomologouschromosomes.Duringmitosis,homologouschromosomesdonot pairsothatdaughtercellsreceiveBOTHhomologues.InmeiosisI,homologouspairsalignandseparatefromone another,leavingonlyonesetofeachindaughtercells. ReviewofMeiosis:GeneticMaterial,ChromosomesandChromatids: ThisisaCONCEPTUALMODEL.Technicallyachromatidisnolongerachromatidwhenitisseparatedfromits centromere(atthatpointtwochromosomesareformed).Buttohelpunderstandwhatishappeningwithwhat structure,thismodelisdevised.

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Themodelshowsanorganismwithtwochromosomes,redandgreen.Eachhasaninitialcontentofamaternally inheritedgreenandred,andapaternallyinheritedgreenandred.GreencodesfromgeneGandredcodesforgene R.PayattentiontothenumberofCHROMOSOMES(ploidy)versusthenumberofCHROMATIDS(geneticcontent) InMitosistheendproductistwodaughtercells,eachwiththesamenumberofchromosomesandchromatids, geneticallyidenticaltooneanother.Theprocessissimply:

4Chromosomes(diploid) 4Chromatids GeneticMaterial1x 4Chromosomes(diploid) 8Chromatids GeneticMaterial2x 4Chromosomeseach(diploid) 4Chromatidseach GeneticMaterialTotal2x,each1x

InMeiosisI,ratherthanhavingallchromosomesalignonthemetaphysealplatesandseparatechromatidsfrom oneanother,homologouschromosomesalignandarepulledapart.Thusly,thereisthesameamountoftotal geneticmaterial(total)ineachoftheproductsofmeiosis1asinmitosis,butthegeneticcompositionisvastly different.Thatis,onlyonechromosome(eitherpaternalormaternal)foreachgeneispresent.

4Chromosomes(diploid) 4Chromatids GeneticMaterial1x 4Chromosomes (diploid) 8Chromatids GeneticMaterial2x 2Chromosomeseach(haploid) 4Chromatidseach GeneticMaterialTotal2x,1xeach

InmeiosisII,thenowhaploidcellswith4chromatidsworthofgeneticmaterialaresplitintohaploidcellswithhalf thegeneticcontentANDhalfthechromosomesastheiroriginalparent.Thisprocessisanalogoustotheprocessof mitosis(thechromosomeshavealreadyduplicatedinto2xchromatids),buthasonlyhalfthegeneticmaterial (mitosiswouldhavebothsetsofhomologouschromosomes),sotheresultisahaploidindividual.

2Chromosomes(haploid) 4Chromatids GeneticMaterialx1

2Chromosomes(haploid) 4Chromatids GeneticMaterialx1

2Chromosomeseach(haploid) 2Chromatidseach GeneticMaterialTotal1x,0.5xeach

REMEMBER:THEREISNOPROPHASEII(theproductsofmeiosis1haveeliminatedthatneed)

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Spermatogenesis.Adiploidcellisconvertedinto4haploidcells.Theprimaryspermatocyteremainswiththesameamountof geneticmaterialaftermitosis.ThesecondaryspermatocyteundergoesmeiosisI,wherehomologouschromosomesseparate, leavingthedaughtercellshaploid.Thechromatidsseparateinmeiosis2,formingspermatids(stillhaploid).Thecompletionof maturationofthespermoccursintheseminiferousvesicles.SpermcompleteMeiosis2.

Oogensis.Adiploidcellisconvertedinto1haploidcellandtwoormoregeneticallyuselesspolarbodies.Theprimaryoocyte, whichisdiploid,undergoesmeiosis1toformasecondaryoocyteandapolarbody.Becauseoftheabnormaldistributionof cytoplasmintoonedaughter,theseconddaughterisinsufficienttocontinueandbecomesadensepacketofgeneticmaterial. ThesameistrueoftheproductofmeiosisII,followingthesecondaryoocytetoproducetheegg.Eggsdonotmatureuntil puberty.OocytesdonotcompleteMeiosis2(heldinmetaphase)untilaspermimpregnatesthecellmembranewithitsnucleus duringfertilization.

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NormalPostZygoticMitosis.Inthiscellall chromosomesalignalongthemetaphyseal plate,andsisterchromatidsseparateto formnormaldaughtercells.

PostZygoticNondisjunction.Afterthezygotehasperformeda mitoticdivision,itispossibleforchromatidstofailtoseparate. Thisresultsinonecellbeingdeficientinageneandonecellbeing Triploidyforonegene.Itisassumedthatinthebolddaughtercell Xandone|codeforthesamegene,whichnowhas3copies.

Mosaicamosaichasastrongerchanceofsurvivalbecausetheyarecreatedbyapostzygoticnondisjunction,and someoftheircellsarenormal,whileothershaveanunequaldistributionofgenes.Theyarekindofnormaland kindofbroken,asopposedtoageneticmishapthathappensduringtheformationofthefirstcell(thegamete). Pathologicalphenotypesarereducedinthesepatients. Seelecturenotesforreviewofpathologies(geneticcause,phenotype,etc.)Imnotgoingtojustcopylecture slides,andshedidntspendthatmuchtimeonthemanyway.

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Thisisasconciseasyouaregoingtogetit.Thereisverylittleexplanation.Dr.Hillwilltakequestions rightoutofhere,almostwordforword.Thiswillnothelpyouunderstandthematerial,butitiswhat youmustknow. I.Spermatogenesis&Spermiogenesisdevelopmentofthesperm: Beginsatpuberty.TestesbegintosecreteincreasedamountsofTestosterone,leadingto(1) developmentofsecondarysexcharacteristics(growth,underarm/pubichair)aswellas(2)stimulates growthanddevelopmentoftestes.Thedevelopmentofthetestiscanbecategorizedby4events: a.maturationofseminiferoustubules b.commencementofSpermatogenesis c.ActivityofSertolicellssupportivecells d.Proliferationofdormantprimordialgermcellsbymitosiscanthendifferentiateintospermatogonia. Thesegermcellsleavebehindonegermcellandonedifferentiatedspermatogonia.

Sertolicellsmanipulatetheearlyspermatidsinto fullonspermatozoa,whicharereleasedintothe lumenofthetestesfortheirjourney.

Asthegermcells(spermatogonia)undergodivisions, theyascend,differentiatingfirstintoprimarythen intosecondaryspermatocytes

Spermatogoniathemselvesarelocatedalongbasalmembraneseminiferoustubulesconnectedto sertolicellbycytoplasmicbridges. Spermatogoniaundergospermatogenesisandspermiogenesis.Theyarenotthesamething. Spermatogenesisisthecreationof4spermatids(spermatogenesisisthecreationofspermatids)from onespermatogoniaviatworoundsofmitosis.Spermatidsareimmatureandcannotdoanythingyet. Spermiogenesisisthedevelopmentfromspermatidtomaturesperm,calledspermatozoa. Spermatogonia Spermiogenesis Spermatozoa(mature) Spermatogenesis Spermatid Spermiogenesis Spermiogenesisisthematurationprocessfromspermatidtomaturespermasgermcellsmove tothelumenofseminiferoustubulesandtotheductusdeferens.Iwishtheykepthistologytogether withembryo,sincethismakesatonofsensewhenyoustudythehistologyofthemalereproductive |T 1 s f o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

Thebasallaminaistheborderbetween everythingelseandtheactionofthe testes.

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system.Withoutit,youwilljusthavetomemorizethewords.WavesofSpermatogenesisoccurthrough theseminiferoustubules.Inhumanmales,eachcycleofSpermatogenesistakesabout64days Sertolicellsarekeyinspermatogenesis.They (1)reducetheamountofgametecytoplasm(spermshouldbesmallandcompactformotility), (2)areresponsiblefortheformationofthesegmentsofthespermatid;thehead(withthegamete nucleusandtheacrosome,acapfilledwithhydrolyticenzymes),midpiece(wherethemitochondriais), andthetail(microtubuleskeyformmotility). (3)inducespermiation,wheresertolicellsbreakcytoplasmicbridgeswithspermatozoareleasingthem intothelumen.
Golgi Acrosome Nucleus ResidualCytoplasm Acrosome Tail

Head Mitochondrion Nucleus Acrosome Nucleus Neck MItochondria Mitochondrion

CapacitationisthefinalstepoffunctionalmaturationforSpermatozoa.Capacitationisessentiallythe activationofthesperm.Itconsistsofchangesintheacrosome(enzymecap)toallowpenetrationofthe ZonaPellucida(aglycoproteincoatsurroundingtheovum). Capacitation CapacitationoccursasthespermatozoamovefromseminiferoustubulesofthemaletotheAmpullaof theOviductinthefemale.ItpreparesSpermatozoaforfertilizationoftheoocyte.Spermproducedin seminiferoustubulesarestoredintheepididymis(coiledregionofvasdeferens).Uponejaculation,as manyas40100millionspermatozoaareexpelledandmixedwithsecretionsfromtheSeminalvesicles, prostate,andbulbourethralglands. Uponexpulsion,thespermmovethroughthevagina,uterus,intofallopiantubes(oviducts),andintothe ampulla,whereSpermatozoatypicallyfertilizetheovuminampulla(expandedregionofthefallopian tubes).Spermintheampullaretainfertilizationviabilityfor13days.Capacitationoccursinthefemale genitaltractasspermcontactssecretionsfromtheoviduct.ThechangesinpHleadtothechangesthat activatecapacitation. II.Fertilization:ACOMPLEXINTERACTIONBETWEENSPERMANDOOCYTE: FertilizationiswheretheSpermforceswaythroughCumulusMass,reachestheZonaPellucida (glycoproteincoat),bindstoahumanspecificglycoproteinspermreceptor,whichinducesthereleaseof degradativeenzymesfromtheacrosome,whichallowsSpermtopenetratetheZonapellucida.

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Capacitationandfertilization Uponreachingtheoocyte,thecellmembranesofthespermandoocytefuse,stimulatingthe releaseofsmallCorticalGranules(justunderoocytemembrane)toreleasetheir contentsinthespacebetweenoocytemembraneandzonapellucida.Materialfromcortical granulesaltersSpermreceptorsinthezonapellucida,therebyblockingreceptorfunction.Thus, thezonapellucidabecomesimpenetrabletospermpreventingPolyspermy.Thisisarapid,almost immediateactivationonceonespermisin,nootherscangetin.Thezonapellucidaisamoatof gasoline.Onlywhentheferrycomesacrossandguidesonespermover,canthatspermcross(theferry isthereceptor).Oncethespermgetsinside,theoocytelightsamatch(thecorticalgranules)andsets themoatonfire(preventinganyoneelsefromcrossing).
Onespermmade it,thoughmany try Pronuclei

MalePronuclei

Nucleusundergoingmitosis(denoted byindentationonthetopandbottom, separationofchromosomesatcenter

FusingPronuclei

FusionofoocyteandspermcellmembranesinducestheoocytetoresumeMeiosisII,completing Meiosis.Thisprocessproducesapolarbodyintheoocyte.Thefirstpolarbody(madeingametogenesis inthefemale)completesitssecondmeioticdivision.Theoocyteisnowthedefinitiveoocyte. Chromosomesoftheoocyteandspermareenclosedinfemaleandmalepronuclei.Pronucleifuseto produceasinglediploid(2n)zygote.Within24hoursafterfusionofthepronuclei,thezygoteundergoes arapidseriesofcelldivisions. Cleavage.Thesecelldivisionsarecalledcleavagesbecausethedivisionsarenotaccompaniedbycell growth,givingrisetosmallerdaughtercells.Normally,acellgrows,doublesitsDNA,growsagain,then splits.Inthisearlyembryonicstage,nogrowthoccursitsmoreimportantthatthecellsdividethanit isthattheygrow,andtheyarealreadycontainedinaconfinedspace(thealteredzonapellucidaakathe |T 1 s f o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

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fierymoat). BarrBodies
ZonaPellucida

Innercellmass

Cavity Blastomere OuterCellmass

Cleavageoccurswithintherigidzonapellucidasothatmultiplecellsareformed.Becausethereisnowhereforthecellstogrow,they becomeprogressivelysmaller(compaction).Eventually,thezygotewillgiverisetotwodistinctlayers:aninnerandoutercellmass Thecellsenclosedinthezonapellucidaarecalledblastomeres.Thesecellsthenformaballofcells calledthemorula.Getreadyfornamechangesandatonofvocabulary(asifyouhaventhadenough) becausekeepingtrackofcellsovertimeisaBEAR. Compaction.Atthe8cellstage,cellcellcontactsdevelopintheoutercells.Theybecomeaconcentric layerofcellsthatseparatestheoutercellmassfromtheinnercellmass.Thispatterncontinuesformost ofdevelopment. III.Implantation: Mechanismofimplantation.Ondays5to6,theembryonicpoleoftheblastocystattachestoand beginstoerode/penetrateintotheuterinemucosa.Penetrationoftheuterinemucosaisaresultofthe actionofproteolyticenzymesproducedbythetrophoblast(alsocalledthesyncytiotrophoblast).Finger likeprocessesofsyncytiotrophoblast(outerlayer)continuetoinvadeanderodetheendometrial epithelium(epitheliumistheouterlayer,likeskin),andtheendothelium(theliningoftissueunderthe epithelium)oftheuterinecapillaries,whiletherestofthetrophoblastiscytotrophoblast.

Syncytiotrophoblastiseating intotheuterineepithelium

Stateoftheuterusatthetimeofimplantation: Thewalloftheuterushasthreelayers:endometrium,myometrium,andperimetrium.Theepithelium coversthethreelayers.Togiveyouatasteofthingstocome,allorgansarelinedbyanepithelium;your |T 1 s f o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

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skinisanepithelium,theliningofyourstomachisanepithelium,theinsideofyourmouthisan epithelium.Donotgetepitheliumconfusedforendo,myoorperimetrium.Theendometriumisinthe secretoryphase,andtheuterineglandsandarterieshavebecomecoiled;thestromaissucculent.Itsa goodthingyouhaventhadhistooranatomyonthisyet,soyouhavenoideawhatthismeans.This wontbeatestquestion. Theendometriumshowsthreesublayers:asuperficialcompactlayer,anintermediatespongylayer andathinbasallayer.Uponfertilization,theendometrialglandsbecomeveryactive,secreting mucusandglycogen,andthearteriesbecometortuous,formingadensesuperficialcapillarybed.Thisis thegraviduterus:theendometriumisedematousandpaleandreadyfortheblastocyst. Iftheoocyteisnotfertilized,theCorpusLuteuminvolutesandchangestowardthemenstrualphase. Dontworryaboutthatrightnow,therewillbealotonmenstruationinhistology&physiology. ImplantationProcess: Implantationissupposedtooccurontheanteriorwalloftheuterus,butcanoccuronany vascularizedmucousmembranetheblastocystfallson.MucousMembranemeanseverythinginside thefemaleforthemostpart.Ifimplantationoccursneartheinternaluterineos(whichiscalled placentaprevia),severebleedingandotherseriousproblemsmayresult.Ectopic(outofplace) implantationsdooccur,andusuallyleadtothedeathoftheembryoandoftentoseverematernal hemorrhaging.Someectopicpregnancieswillgototerm(e.g.placentaprevia),mostwillnot. Ectopicsitesofimplantationinclude: Abdominalpregnancyimplantationintheabdominalcavity,thepouchofDouglas(rectouterine pouch),onamesenteryorthesurfaceofakidney.Thesegiverisetolithopedians,orstonebabies. TubalpregnancyimplantationintheoviductorFallopiantube(infundibular/fimbrial),ampullary, isthmicandinterstitialregions. Primaryovarianpregnancyimplantationontheovaryitself. Placentapreviaimplantationontheloweruterinesegmentorontheinternalosoftheuterus. Secondaryimplantationmayoccur;tubalpregnanciesareoftenexpelledandendupasabdominal pregnancies.Simultaneousimplantationisadangerouspossibility:anormalintrauterinepregnancymay mask,foratime,thepresenceofanectopicone.Thiscanonlyoccurwhentwooocytesarereleasedand arefertilizedseparately(asinthecaseoffertilitydrugadministration). IV.EarlyAbortions: AnAbortionisanyterminationofpregnancybeforetheperiodofviabilityhasbeenreached(thatis, before20weeksofgestation).Earlyabortionsarecommonevents,whichoftenoccurbeforepregnancy isrecognized,andhencegounnoticed,oraremistakenfordelayedmenstruation.Onethirdtoonehalf ofallzygotesneverlivetoimplant,andhalformoreofthosethatdosoonabort. Almostallabortionsduringthefirstthreeweeksarespontaneous.Chromosomalabnormalitiesaccount for1/2ofspontaneousabortions(nondisjunctionduringoogenesisisonemechanism).Some Teratogens(agentsinducingorfavoringcongenitalmalformations)actinginthefirsttwoweeksmay causeearlyabortions. |T 1 s f o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

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V.SecondWeekofDevelopment/FormationofBilaminarEmbryoorGermDisc: Afterfertilization,thezygotewillundergocleavage(aseriesofrapidmitoticdivisions).Theoverallsize ofthemassofcellsincreasesverylittlewhilethenumberofcellsincreases(compaction).Theballof cellsisknownasamorula. Blastocystformation.Spacesforminthemorula,dividingthecellmassintotwopart:the (1)trophoblast(outercellmass),whichwillgiverisetothefetalcomponentoftheplacenta,andthe(2) innercellmass,whichwillgiverisetotheembryoproper.Acavityformsbetweentheinnerandouter cellmassesandisfilledbyfluid.Fivetosixdaysfollowingfertilization,theoutercelllayerofthe blastocystwilldifferentiateintotwolayers,aninnercytotrophoblast(cellulartrophoblast)andanouter syncytiotrophoblast(syncytium).Iwanttopointout,again,thatthetrophoblast(theoutercelllayer) becomestwolayers:thecytoandthesyncytiotrophoblast.Thecytotrophoblastand syncytiotrophoblastwillformthefetalcomponentoftheplacenta. Theinnercellmass,whichhasnotbeengivenaname,dividesintotwoflattenedlayersofcells,the epiblast(ectoderm)andhypoblast(endoderm).Thisisthebilaminarembryothatwasthesubject headingfortodayslecture.

Theprochordalplate.Itistherostral(head)areaoftightappositionbetweentheendoderm(hypoblast) andectoderm(epiblast).WehaveamusicgroupcalledRostralCaudal,anditiswhatIusetokeepthe twowordsstraight.Rostralcomesfirst,andtheheadismoreimportant/higherup,soitcomesfirst. Thusrostralmeanstowardsthehead,andcaudalmeanstowardstheanus.Theprochordalplateisthe siteofthefuturemouthandakeyorganizerregion.Itisanexampleoftissueaffinity,animportant developmentalprinciple. Theconnectingstalkisabridgeofextraembryonicmesodermfromtrophoblasttoembryo.Ughwhat thehelldoesthatmean?Basicallyitsaconnectionbetweenmomtobaby,madefromstuffthatisnot thedevelopingembryo(extraembryonic).Mesodermisthismagicalsubstancethatcanbecomejust aboutanything.Theconnectingstalkistherouteofthefutureumbilicalbloodvessels. VI.SecondWeekofDevelopment(Timetable):Thisislessimportant.Hilldoesntlikequestionslike whendoesthishappen,butthatdoesntmeanhecannotaskyou.Whathappensandinwhichorderis |T 1 s f o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

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moreimportantthanthedayithappenson.UseDr.HillsMACBABYsoftwareforthisportion.Youhave toknowthisstuff,butthelevelofdetailandvocabularyisintenseafterwhatyouvejustgonethrough. Iveputitinhereforreference,butusemacbaby. 8thdayofdevelopment:Differentiationoftrophoblastintocytotrophoblast&syncytiotrophoblast. Differentiationoftheembryoblast(innercellmass)intoepiblast(ectoderm)&hypoblast(endoderm). Formationofamnioticcavity. 9thdayofdevelopment: 1.Embedmentofblastocystandclosureofpenetrationdefect(plug)intheendometrium.Delamination ofHeuser'smembranefromcytotrophoblast.Formationoftheprimitiveyolksac[endoderm]. 1112thdaysofdevelopment: Establishmentoftheuteroplacentalcirculation:Penetrationofsyncytiotrophoblastcellsinto stroma/erosionofendotheliumofmaternalcapillaries(sinusoids)andentranceofmaternalbloodinto thelacunarspacesofthetrophoblast. Originoftheextraembryonicmesodermfromthecytotrophoblast.Cavitationofextraembryonic mesodermandformationoftheextraembryoniccoelom(chorioniccavity). Extraembryonicsomatopleuricmesoderm(linescytotrophoblastandamnion)andextraembryonic splanchnopleuricmesoderm(coversyolksac). Growthofbilaminargermdisc:spreadofendodermtoformHeuser'smembrane. 13thdayofdevelopment: Formationofprimarystemvilli(acoreofcytotrophoblastandoutersyncytiotrophoblast.) Involutionofprimaryyolksacandappearanceofsecondaryordefinitiveyolksac. Expansionofextraembryoniccoelom/chorioniccavity. Establishmentofthechorion:alaterstageoftheoriginaltrophoblasticcapsule,towhichalining ofextraembryonicmesodermhasbeenadded. Thechorionicplate(extraembryonicmesodermliningtheinsideofthecytotrophoblast)andits connectiontotheembryoviatheconnectingstalk. Thechorionisaprotectiveandnutritivemembrane:itshieldstheblastocystwithinandthrough itsliningofmesodermandconnectingstalkandoffersarouteforbloodvessels(umbilical vessels)toruntoandfrombetweentheembryoandthechorionicvilli(primitiveplacenta) Amnioticcavitybeginstoformasfluidfilledspacescoalesceintoonelargecavity.Amnioblasts, cellsoflining,arederivedfromectoderm.

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TogetANYideaaboutwhatthislookslikein3DyouMUSTUSEDrHillsMacBaby.Thequestionswillbefrom thesewords,butyourunderstandingwillcomeonlyfromMacBaby. I.FormationoftheTrilaminarEmbryo Duringthethirdweek,theembryoisdevelopingrapidly,andthisdevelopmentischaracterizedbytheformationof theprimitivestreakandthethreegermlayersfromthebilaminardisc. A.FormationofBilaminarEmbryo.Afterimplantation,spacesbegintoappearbetweentheinnercellmass,and thesespaceswillcoalescetoformtheamnioticcavity.Changesareoccurringintheinnercellmasssothatitis transformedintotheembryonicdisc(aflattenedcircularplateofcells).Thisdiscinitiallyconsistsoftwolayers:(1) theepiblast(ectoderm),composedofhighcolumnarcellsthatarerelatedtotheamnioticcavityand(2)the hypoblast(endoderm),whichiscomposedofcuboidcellsthatlienexttotheblastocystcavity. B.Gastrulationtheprocessbywhichtheinnercellmassisconvertedintoatrilaminarembryonicdisc. Gastrulationbeginsattheendofthefirstweek/beginningofthe2ndweekofdevelopmentasthehypoblastand epiblastareformedandiscompletedbytheendofthethirdweek.Inthethirdweek,athickenedmidlinebandof epiblastic(ectodermal)cells,knownastheprimitivestreak,beginstodevelopinthecaudalaspectofthe embryonicdisc.Theprimitivestreakformsasaresultoftheproliferationandpilingupofepiblasticcellsalongthe posterioraspectoftheembryonicdisc(primitiveknot,primitivepit).

Primitivegrooveadepressionthatformsinthemidlineoftheprimitivestreak.Epiblasticcellsmigratefromthe peripherytothemidline,pileuptoformtheprimitivestreak,cellsinvaginate,andmovetothedeepaspectofthe primitivestreak,breaklooseandmigraterostrally,caudally,andlaterallybetweenthetwooriginallayersofthe bilaminardiscformingathirdlayer,theintraembryonicmesoderm. Assoonastheprimitivestreakbeginstoproduceintraembryonicmesoderm,theepiblastandhypoblastare referredtoastheectodermandendodermrespectively. Mesodermalcellsallofthecellsthatarisefromtheprimitivestreak.Thesecellsareprecursorstoavarietyofcell typesthatwillformconnectivetissues(bone,cartilage,bloodandmuscle,etc.). C.FormationoftheNotochord.Thenotochordalprocessisamidlinecellularcordformedbymesodermal cells,whichmigraterostrallyfromtheprimitiveknot.Itwillgrowrostrallybetweentheectodermandendoderm untilitreachestheprochordalplate(oropharyngealmembrane).Theprochordalplateisacircularareacomposed ofcolumnarendodermalcells(whicharenormallycuboid),whicharetightlyappliedtotheoverlyingectoderm. Thiswillultimatelyformtheoropharyngealmembrane,thefuturemouthregion.Somemesodermalcellsmigrate

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laterallyandcraniallyfromtheprimitivestreakbetweentheectodermandendoderm.Thesemesodermalcellswill continuetomigratelaterallyandcraniallyuntiltheyreachthemarginsoftheembryonicdiscandwilljointhe extraembryonicmesoderm.Somecellsoftheprimitivestreakmigratecraniallyoneachsideofthenotochordal processandaroundtheprochordalplate,wheretheymeetcranially.Thisareaisreferredtoastheprimitive cardiogenicarea,thesiteofthefutureheart.

TheNotochord=arodofcellswhichdevelopsfromthenotochordalprocess.Thenotochordisimportantbecause itdefinestheprimitiveaxisoftheembryoandgivestheembryosomerigidity.Asthenotochordalprocessgrows cranially,theprimitivepitwillextendintoit,formingthenotochordalcanal(lumen).Thenotochordalprocessis nothingmorethanacolumnofcellsthatextendsfromtheprimitiveknottotheprochordalplate.Asthe notochordalprocessdevelops,itsdeepercellsfusewiththeunderlyingendodermanddegenerate.Asaresult,an openingappearsalongthefloorofthenotochordalprocessandallowsthenotochordalcanaltocommunicatewith theprimaryyolksac. Thenotochordalprocessflattensout,formingagroovedplateknownasthenotochordalplate,whichwillfold uponitself,beginningatitscranialend,toformasolidcolumnofcells,thenotochord.Thenotochordisacolumn ofcellsaroundwhichthevertebralcolumnforms.Itinducestheoverlyingsurfaceectodermtoformtheneural plate(theprimordiumofthecentralnervoussystem).Therearetwoexceptionstothistrilaminararrangement. Theyaretheoropharyngealmembrane(rostral)andcloacalmembrane(caudal),thesiteofthefutureanus,which arebilaminar.Bytheendofthe3rdweek,theectodermandendodermareseparatedbytheintraembryonic mesoderm,exceptatthesetwosites.Ultimately,theprimitivestreakdegeneratesintoaninsignificantstructurein thesacrococcygealregion,whichmaysometimespersistandgiverisetoatumorknownasateratoma. D.Neurulation.Neurulationistheprocessbywhichtheneuralplatedevelops,folds,andformstheneuraltube. Thisprocessbeginsinthethirdweekandisfinishedbytheendofthefourthweek,duringwhichprocessthe embryoisreferredtoasaneurula. Neuroectodermistheectodermoverlyingthenotochord,whichisinducedbythenotochordtothickenandgive risetotheneuralplate.Neuroectodermwillultimatelygiverisetothecentralnervoussystem.Theneuralplate firstbeginstoformrostraltotheprimitiveknotanddorsaltothenotochordandwillextendasfarcraniallyasthe oropharyngealmembrane.Theneuralplatewillinvaginatealongitscentralaxis,formingtheneuralgroove.Neural folds(elevations)appearoneachsideoftheneuralgrooveandwillmovetowardsthemidlineandfusewitheach othertoformtheneuraltube.Keepallofthoseneuralsstraight.Astheneuraltubeforms,itlosescontactwith theoverlyingsurfaceectodermandsinksintotheunderlyingmesoderm. Astheneuraltubeforms,someoftheneuroectodermalcells(whichoriginallylieclosetothecrestofeachneural fold)losetheiraffinityforotherneuroectodermalcellsandbegintomigrateawayfromtherestofthe

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neuroectodermalcells.Thesecellsarereferredtoasneuralcrestcells.Neuralcrestcellsmigrateventrolaterally (outtothesideandtowardsthefront)oneachsideoftheneuraltubeandinitiallycometoliebetweentheneural tubeandthesurfaceectoderm. II.DevelopmentofBodyForm A.AllometricGrowth.ThegermlayersundergoAllometricgrowthofthethreegermlayers.Thismeansthatnot allgermlayersgrowatthesamerate.Theorderofthethreegermlayersfromdorsaltoventralare:ectoderm, mesoderm,thenendoderm.Theendodermallayerformsbaseforgrowthoftheothertwolayers. B.Headandtailfolds.Inthethirdweek,thetrilaminarembryoisaflatdiscthatisbroaderrostrallyandnarrower caudally.Themainfeatureistheprimitivestreak.Asorgansystemsdevelop,theembryochangesshapethrougha processcalledmorphogenesis.Becauseofrapidgrowthduringthisperiod,exposuretoteratogensresultinmajor congenitalmalformations.Theectodermalandmesodermallayersgrowveryrapidlyandsoonovergrowtheslow growingendodermalbase.Thisresultsinaventralfoldingoftheembryoattherostralandcaudalends,forming theheadandtailfolds.Therapidgrowthoftheneuraltubealsoplaysamajorroleincraniocaudalfoldingofthe embryo. Therearetworegions,whichremainbilaminar(ectodermandendoderm):theoropharyngeal(rostral)andthe cloacal(caudal)membranes.Thesetworegionsarerelativelystationary(duetolackofendodermalgrowth)and willformthemouthandtheanus. C.Establishmentofforegut Bytheendofthethirdweek,thenotochordinducesoverlyingectodermtoformneuralfolds,whichwillfuse, formingthebrainandspinalcord.Themostrostralpartofthebrain(forebrain)proliferatesrapidlyandovergrows thestationaryoropharyngealmembrane,whichservesasafulcrumaroundwhichtheforebrainrotatesventrally. Thisfoldingpullsthemorerostralportionoftheyolksacintotheembryotoformtheforegut.Theforegutwilltake apositionbetweenthedevelopingbrain(rostral)andthedevelopingheart(caudal).Theoropharyngealmembrane separatestheforegutfromtheamnioticcavity,butwillruptureattheendofthirdweekallowingtheamniotic cavityandguttocommunicate. D.Establishmentofcardiogenicarea. Earlyangiogenesisoccursintheextraembryonicmesodermoftheyolksacandallantois.Thisresultsin:(a) Formationofbloodcells,and(b)Formationofendotheliallinedspaces(primitivebloodvessels). Intraembryonically,angiogenesisoccursjustrostraltooropharyngealmembraneintheprimitivecardiogenic area.Bloodislands(cellclustersthatcanmakeblood)formandcavitate,givingrisetoprimitivebloodvessels. Primitivebloodvesselscoalescetoformtwolongitudinalhearttubes. Thecardiogenicareaisinitiallyrostraltotheoropharyngealmembrane,butitrotates180oventrallyandcaudally (tothefrontandoverthehead),undertheprospectiveheadregionofembryo(duringformationofheadfold)and nowliescaudaltotheoropharyngealmembrane. E.Developmentofseptumtransversum.Theseptumtransversumdevelopsfromextraembryonicmesodermjust anteriortotheprimitivecardiogenicregionandwillrotate180oalongwiththecardiogenicarea,butwillcometo liecaudaltocardiogenicarea,underprospectiveheadregion.Septumtransversumgivesrisetotheventralportion ofdiaphragm.Thatstheimportantpartabouttheseptumtransversum. F.Developmentofthehindgut: Tailfolddevelopsatthecaudalendoftheembryoshortlyafterformationofheadfold.Thecaudalpartofneural tubeovergrowsthestationarycloacalmembrane,andthewholeregionrotates180o.Thecaudalportionofthe

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yolksacisincorporatedintotheembryoasthehindgut. Thecloacaformsastheterminalportionofthehindgutdilatesandisseparatedfromtheamnioticcavitybythe cloacalmembrane.Theallantois,asmalldilationjustcaudaltothecloaca,hasrotated180oandwillbe incorporatedintotheumbilicalcord. G.Developmentoflateralbodyfolds: Thereisalsosignificantlateralgrowth(sideways)oftheembryo,whichresultsinthelateralfoldingoftheembryo. Thesomatopleureoneachsidefoldsdowntowardsthemidline,pushingtheedgesoftheembryonicdisc ventrally,ultimatelyformingacylindricalembryo.Themiddleportionoftheyolksacisincorporatedintothe embryo,givingrisetothemidgut.Thelateralfoldingoftheembryoalsoresultsinthemedialmovementofthe twolongitudinalhearttubes.Thesetubes,whichwillformtheheart,wereoriginallylocatedrostraltothe oropharyngealmembrane,butnowliecaudaltotheoropharyngealmembrane.Shortly,thetwolongitudinalheart tubeswillfuseinthemidline,formingasingleendocardialhearttube. Theestablishmentoftheforegutandhindgutareprimarilytheresultofheadandtailfoldformation,whilethe midgutisproducedbythelateralfoldingandwillretainitsconnectionwiththeyolksac.Thisconnection willrapidlyconstrictandelongatetoformthevitellineduct. H.Formationoftheumbilicalcord. Theamnioticcavityexpandsmorerapidlythantheembryo,andasaresultit,overgrowstheembryoandchorionic cavity.Theamnionenvelopstheconnectingstalkandyolksac,compressingthemtoformtheprimitiveumbilical cord.Atitsdistalend,theumbilicalcordcontainsthevitellineduct(yolkstalk)andumbilicalvessels.More proximally,itwillcontainthemidgutandallantois. I.Formationoftheintraembryoniccoelom. Theintraembryoniccoelomformsfromsmallisolatedspacesinthelateralplatemesoderm,whichcoalesce formingasinglehorseshoeshapedcavitythatsplitsthelateralplatemesodermintotwolayers:somaticand splanchnicmesoderm.Somatic(parietal)mesodermiscontinuouswiththeextraembryonicmesodermliningthe amnion.Splanchnic(visceral)mesodermiscontinuouswiththeextraembryonicmesodermliningtheyolksac. Withcontinuedlateralfoldingoftheembryo,thetwocomponentsoftheintraembryoniccoelomarebrought togetherontheventralsurfaceoftheembryo,formingasinglecontinuouscavity.Theintraembryoniccoelomwill giverisetothefollowingbodycavities:(a)pericardialcavity,whichhousestheheart,(b)pleuralcavities,which housethelungs,(c)peritonealcavity,whichhousestheGIorgans. J.Thegastrointestinaltract. 1.TheGItractisderivedfromforegut,midgutandhindgut. 2.Isactuallyatubewithinatube

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ANATOMY:August17thSpinalCordDevelopment

Thiswasalotofreviewfrombothembryopriortothisandfromtheanatomylectureonthevertebralcolumn.If youvebeenfollowingalonguptothispoint,thisshouldhavejustbeenareinforcementofinformationthatyou alreadyknowwithafewmoretermsthrownin.Theendofthislecturebringsuphebbiansynapsingandthe importanceofneuralcrestcells. Objective1:BeabletodefineNeuralPlate,NeuralFold,NeuralUbe,Neuropores,Neurulationandthe approximatetimeinhumanpregnancythisoccurs,theneuralcrestcellsandtheirmigration,deriviativesofthe neuralcrest. Duringgastrulationthenotochordformsfrommesodermalcellscalledthemesnenchyme.Itgrowsfromthe primitivepitinthelayerofectoderm,growingrostrallyandcaudally,extendingthepharyngealandcloiacal membrane.Inhumans,thenotochordisacrucialstructure,notforthestructureitprovides,butforitsinductive nature.In1,weseetheinductivenatureofthenotochord.Intheectodermabove,theneuralgrooveforms,along thebackoftheembryo,rostraltocaudal.ThesecellsarethefutureCNSandwillformtheneuraltube.Flanking theneuralgroovearetworidgescalledtheneuralfold,whichwillclose(asdepictedinfigure2)aroundthetop ontoitself.Itdoesthisinthecenteroftheembryosbackandmovesrostrallyandcaudallysimultaneously.As depictedinfigure2aswell,thereareneuralcrestcellsthatridetheneuralfold.Asthetwosidesofectoderm cometogether,theneuralcrestcellswillpinchoffintomesoderm,allowingforclosureoftheneuraltube.Surface ectodermdestinedtobecomeskinalsopinchesoffandsealsthenacentnervoussystembelowaprotectivelayer. Thereddotinfigure2isthenotochord.NeuralCrestcellswilleventuallybecomethespinalganglionand peripheralnervoussystemwhiletheyneuraltubewillbecomethecentralnervoussystem.Neighbooring mesodermwillformthevertebralcolumnandincorporatethenotochordtoformthenucleuspulposusofthe intervertebraldiscs.Sinceweareformingatube,andtubeshaveopeningsateitherend(callednuclearpores)itis criticalthattheseeventuallyseal,elseexposethenervoussystemtotheexternalenvironment.Neurulationoccurs ataboutweek3andtakesuntiltheendofweek4tocomplete.Keepinmindthatbodyfoldingisoccurring simultaneously,andallotherdevelopmentalaspectsareoccurring.

Ectoderm Neural Crest

Neural Groove

Neural Groove FutureSkin

Neural Crest

Neural Tube

Neural Pore

Future CNS

Future PNS

FORDISORDEROFCLOSUREOFTHENEURALTUBE,CALLEDSPINABIFIDA,REFERTOTHEVERTEBRAL LECTURE:ANATOMYAUGUST17thVERTEBRALCOLUMN.Eatfolicacid=dontgetthesebirthdefects

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ANAT TOMY:Au ugust17t thSpinal lCordDe evelopme ent

Objective e2:Beableto odescribene euronalmitos sis,migration nanddifferen ntiation,andtheirdisease es A. Fa ateoftheNe euralTube
The eMitoticDance e.Neuroepithe elialcellsform mthewallofth he earl lyneuraltube.Thesethengiv verisetoearly yneuroblastsborn b alon ngtheventricu ularsurface(th hesurfaceonthelumen)and d mig grateawayfrom mthelumenbecomingneuro ons.Thedanc ceis that ttheseneural cellsriseaway yfrom,thenre eturnto,theluminal face etodivide,fina allyformingne euroblasts.Neu uroblastsarepost p mito oticandtheref forewillnotdi ivideagain.Forthemostpar rt, new wneuronsdonot n developinthebornhuma an.Asmorean nd mor recellscomein ntoexistenceat a theluminalsurface,crowd ding occu urs,andthene euroblastsride ethescaffoldin ngcreatedbyradial r glialcellstotheoutersurface,contributing c toneuronal mig gration. Or rganizationofSpinalCord. Therearetwozones z of proliferationofneurons, n onedorsal d andoneventral(asthe e up psidedownco opyattemptsto oshowaboveinfigure1).Th he Ala arPlateisdors salandformsacontinuouscolumn c of sensoryneurons softhedorsalhorn.TheBasa alplateis ventralandisprimarilymotorandpreganglio onicautonomic thatformstheco ontinuouscolu umnofmotorneurons n ofthe e ve entralandlater ralhorns.Itisthe t glialcellsthatdirect mi igrationawayfrom f thelumentowardstheplates.

THIS SISTHECENT TEROFTHETUBE T

B. Fa ateoftheNe euralCrest
De erivation fromNeuralCrest.While W thepictu uretotheleftlooks lik ketherostralcaudalneuraltu ube,itsreferen ncesreferonly yto theneuralcrestcellsthatpinch hofffromtheectodermduring primaryneurala ation(tubeform mation).Neura alCrestswillin nvade theperipheryan nddifferentiate eintotheentir rePNS.Theywill w dif fferentiateinto otheSchwann ncellsthatprovidetheinsula ator my yelinsheath,dorsal d rootgan nglioncells,autonomicganglia, willformtheent tirenervoussy ystemofthegu ut(entericnerv vous system),andwillcreatetheen ndocrineextensionofthener rvous sys stembyformin ngandinnerva atingtheadren nomedullaryce ellsof theadrenalglands.Thisconcep ptisdiscussedlater,butbasi ically asympathetic s re esponseisactiv vatedimmedia atelyneuronall ly, ndsustainedch hemically,with hcatecholamin nerelease,sign naled an by yelectricalactiv vity.

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NeuralCrestFailures:HirschsprungsDiseaseandWaardenburg Thisisadiseasecausedbytheinnappropriateformationoftheentericnervoussystemofthegut.Theenteric nervoussystem,amongstotherthings,controlsperistalsis(therythmiccontractionandrelaxationofsmoothe musclethatforcesfoodbolusesalongtheGItract).Whiletheexactcauseofthediseaseisnotknown,whatis knownisthatregionsoftheGItractarenotinnervatedbytheentericnervoussystemwhichresultsinalackor peristalsis,whichcreatesamassivebowelobstructionwhichisfatal.Itisthoughttobeaproblemwithinthe innervationofthegut.GlialDerivedNeurotrophicFactor(GDNF)promotesmigrationofneuralcreststemcellsto theirtarget.ThegeneRetwhichcodesareceptorontheneuralcrestcellsrespondstoGDNF.IfeitherGDNForRet fail,theneuralcrestcellswillnotmigratenorformconnectionswheretheyshould.Regionsofuninnervatedtissue canbesurgicallyremoved. TypeIWaardenburghaveawhiteforelock,congentialdeafness,anddifferentcoloredeyes.Itiscausedbya mutationofaregulatorygeneexpressedbyneuralcrestcellscalledPAX3 Objective3:EstablishmentandRefinementofneuronalconnections

Connections.Duringdevelopmenttherearelongandshortacting
messagessenttothedevelopingneuronbythetargetcell.Whileitis notwellunderstood,chemoattractionandchemorepulsionactover longdistances,andcontinuetheirsignalingevenifthedeveloping landscapechanges(cuttingadevelopingsensoryneuronwillstill innervateitstarget,eventhough,intime,itcrossesdifferentstructures fromitsnormaldevelopment).WhatwassaidinlecturewasthatNerve GrowthFactor(NGF)andGlialDerivedNeurotophicFactor(GDNF)are (1) someoftheimportantfactors.Whatiskeyisthatmoreneurons developthanarefoundintheadult.Manyneuronsdieasaresultof programmedcelldeath.Survivalisactivitydependentandispromoted byneuotrophicfactors.HebbianSynapsingstatesthatcellsthatfire togetherwiretogether(thuspersistandsurvive)whilecellsoutof sync,losetheirlink(andsufferprogrammedcelldeath).Figure2 (2) demonstratesthisinacartoon,wherethespikesof1and2are concurrentand3isnot,1and2persist,3dies.Cellswithoutsynapses,dieaswell. NGFisthesurvivalfactor,itis bytissuesinnervatedbythesympatheticnervoussystemandsmallsensoryneurons.Infact,itis produced tohaveperipheralnerveregenerationinthepresenceofNGF.Thecellknowsaconnectionhasbeen possible madeor lostthroughtwomechanisms.Fastaxonaltransporttransportsgrowthfactorsandproteinsbothinand out(transmission ofNGFtosoma,forexample).Slowaxonaltransportisstructuralcarryingnotjustmessages, butbuildingblocks.Itisabout2mm/dayandhappenstobetherateofnerverengeration.

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EmbryoAugust18thDevelopmentofMusculoskeletalSystem
I.DevelopmentoftheSkeletalSystem: Theskeletalsystemdevelopsfromthemesodermalgermlayer,whichappearsduringthethirdweekof development.Mesodermalcellswillgiverisetoalooselyorganizedtissueknownasmesenchyme (embryonicconnectivetissue).Mesenchymalcellsarepluripotent,meaningtheyhavetheabilityto differentiatedownseveraldifferentpathways.Onecellcanbecomemanydifferentcelltypes. Neuralcrestcellsintheheadregioncandifferentiateintomesenchymalcellsandmigrateintothe branchialarchestoformacartilagebarandwillultimatelyparticipateintheformationofthe bonesoftheface. Theembryonicmesodermcanbedividedintothreebasicregions,proceedingfrommedialtolateral: 1)Paraxialmesodermthickeningofmesodermadjacenttothedevelopingnotochordalprocess, formingalongitudinalcolumnofcells.Thiscolumnofmesodermiscontinuouswiththeintermediate andlateralmesoderm.Inthethirdweek,theparaxialmesodermundergoessegmentationintosomites (pairedcuboidbodies).Thefirstpairofsomitesdevelopjustcaudaltothecranialendofthenotochord, andnewpairsofsomitesappearinsequencefromcranialtocaudal.Duringthesomiteperiodof developmentabout38pairsofsomitesdevelop.Somiteswillgiverisetomostoftheaxialskeleton (vertebralcolumnandtheribs). ParaxialMesoderm=Somites=AxialSkeleton. 2)Intermediatemesodermislocatedbetweentheparaxialmesodermandthelateralmesodermand hasverylittletodowiththeformationoftheskeletalsystem,butismoreconcernedwiththeformation oftheurogenitalsystem,includinggonads,ducts,andaccessoryglands. 3)Lateralplatemesodermwillsplitintotwosegmentsastheintraembryoniccoelomforms.The twolayersarethemesodermofthesomatopleure,whichiscontinuouswiththeextraembryonic mesodermliningtheamnionandthemesodermofthesplanchnopleure,whichiscontinuouswiththe extraembryonicmesodermcoveringtheyolksac.

Visualizationoftherelationshipofthelateral,intermediateand paraxialmesodermintheearlyembryo.Paycloseattentionto coelomicspacesandtheneuralgroove Alittlelaterindevelopment.Theneuraltubehasformed,the coelomicspaceshaveopenedandthelateralmesodermhasbeen splitintosomaticandsplanchnicmesoderm.

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Somitesappearaspairsofbeadlikeelevationsalongthedorsolateralsurfaceoftheembryo.Shortly aftersomitesform,theirventralandmedialwallslosetheirorganizationandbreakupintotwomasses ofcells.Themoreventromedialmassisreferredtoasasclerotome(larger)andthedorsolateralmassis thedermomyotome(smaller).Thesclerotomicmassmigratesbetweenthenotochord,the neuraltubeandtheprimitivegutandwillfinallysurroundthenotochord.
Thispicturehasalotin it,butfocusonlyonthe importantstuff.This demonstratesthe developmentofa somiteintoa scleratome,whichthen migratesaroundthe neuraltube.The notochordisthespinal cord,thesclerotome becomesthebone aroundthespinalcord.

Othermesodermalcellsalsomigratealongwiththesclerotomeandtakeupapositionaroundthe notochord.Thesemesenchymalcellseventuallybecomesurroundedbysclerotomiccellsknownasthe perichordaltube(theyformatubearoundthetube).Eachsclerotome,asitsurroundsthenotochord, consistsoflooselyarrangedcells.Atthehead,thereisacraniallylooseperichordaldiscand atthebackend,packedcellscaudallydenseperichordaldisc.Withtheformationoftheperichordal discs,thenotochordbeginstoshowsegmentation,enlargingwithinthedenseperichordaldiscsand narrowingwithinthelooseperichordaldisc.

Eachdenseperichordaldiscandtheenlargedportionofthenotochordwithinitwillformthe intervertebraldisc.Cellsofthedenseperichordaldiscabovejointhecellsofthelooseperichordaldisc belowtoformthebodyofeacharch.Therefore,eachcentrumisbelievedtodevelopfrom twoadjacentsclerotomesandisthusanintersegmentalstructure. Theportionofthenotochordsurroundedbythevertebralbodywilldegenerate,buttheregionofthe notochordoutsidethevertebrawillexpandtoformthenucleuspulposus(thegelatinouscentralportion oftheintervertebraldisc).Theannulusfibrosusisderivedfromthedenseperichordaldiscandis |T 1 F o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

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composedoffibersarrangedinacircularmanneraroundthenucleuspulposus.Thesetwocomponents constitutetheintervertebraldisc.Sometimesremnantsofthenotochordpersistinsomepart oftheaxialskeletonandgiverisetoachordoma(baseoftheskullorinthelumbosacralregion).
Thenervemigrates throughtheloosely packedtopand denselypacked bottom.Theregions ofcellsbetween growingnervesfuse toformthe vertebrae.The myotomedevelops intomuscles,which aretheninnervated bythenerves.

Thearchofthevertebraisformedbymesenchymalcellsfromthedensecaudalpartofthesclerotome thatsurroundtheneuraltube.Cellsinthecentralaspectofthedevelopingarcharederivedfromthe loosediscandwilldegeneratetoformavertebralforamen. Developmentoftheribs. Ribblastema(preribstructures)arisefromlateralprojectionsofthedenseperichordaldisc(fig.156A). Onearisesoneachsideoftheintervertebraldisc.Astheribprimordiumgrowslaterally,itarches dorsallyandcaudally(towardsthebackandthehead)andwillultimatelycontactthetransverseprocess ofthevertebralarch. Thus,theultimatederivativesofthesclerotomeare:centrumofthevertebra,neuralarch,rib,andthe annulusfibrosus. Chondrificationofthevertebraeandribs(6thweek). Chondrificationmeansturningintocartilage.Thisprocesshastohappenfirst,wherechondrocytes (cellsthatmakecartilage)develop.Oncetheyarethere,ossificationturningintobonecantakeplace. Twocentersofchondrificationdevelopwithinthecentrumofthevertebra.Atthesametime,eachhalf ofthevertebralarchandeachribprimordiadevelopachondrificationcenter.

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Ossificationofthevertebraeandribs. Primaryossificationcentersbegintoformduringthe8thweekofdevelopmentatthesamesitesthatthe chondrificationcentersdeveloped.Initially,twoossificationcentersdevelop(oneventralandone dorsal),ineachcentrum,butfusetoformonecentralcentercalledtheprimaryossificationcenter.A primaryossificationcenteralsodevelopsineachvertebral(neural)arch,andossificationproceeds dorsallyintothelamina,ventrallyintothepedicle,laterallyintothetransverseprocessandintothe articularprocesses. Secondaryossificationcentersdonotbeginto appearuntiltheonsetofpubertyandcontinueto appearuntilapproximately20yearsofage.Each typicalvertebrahas5secondaryossificationcenters: (1)tipofthespinalprocess,(2)theendofeach transverseprocess,(3)twoannular(rim)epiphyses, (4)onecephalic,and(5)onecaudal

Developmentofthesternum. Thesternumbeginsasapairofmesenchymalbandsthatdevelopintheventrolateralbodywall.These platesofmesenchymechondrifytoformtwosternalplates.Theplateswillfuseinacraniocaudal directionandthecranial6or7costalcartilageswillattachtothem.Pictureazipper,zippingfromthe topdown,thenthegrowingribsinsertingthemselvesintotheonezippedplate.

Ossificationcentersappearpriortobirthwiththeexceptionofthexiphoidprocess,whichossifies sometimeduringchildhood.

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II.Developmentofthemuscularsystem: SkeletalMuscle Themuscularsystemdevelopsfromthemesodermalgermlayer.Muscledevelopmentisfirstindicated bytheelongationofthenucleiandcellbodiesofmesenchymalcells(derivativesofsomites)toform myoblasts.Mesenchymecanbecomelotsofthings.Whenitbecomesmyoblasts,itsonitswaytothe muscularsystem.Wecallthatdifferentiation.SomiteMyotomeMyoblastmyotube.

SomiticEpithelium=SomitesMyotomes.Myotomeshavemyogenicprogenitorcellsinthemthatthenbecomemyoblasts.Myoblastsform myotubes.Myotubesthenformmyofibers.

Somitesdifferentiateintomassesofcellsknownasmyotomes.Cellsofthemyotomesplitoffand becomeelongatedandspindleshaped(myoblast).Myoblastsdifferentiateandfusewitheachother formingalong,multinucleatedcylindricalstructuresknownasmyotubes.Muscleswilleventuallybe formedbythecontinuedfusionofmyotubes. Myofilaments(actin/myosin)begintoformshortlyafterthefusionofmyoblasts.Myofilamentsform myofibrils,whichbecomeevidentinthecytoplasmofthemyotubesbytheendofthethirdmonth, formingcrossstriations.Musclecellsarereferredtoasmusclefibersbecausetheydevelopfromthese longmyotubesandhaveanelongatednarrowformthatresemblesfibers.Notallstriatedmusclefibers developpriortobirth;somefiberswilldevelopduringthefirstyearfollowingbirth. SomitesandSomitomeres Manyskeletalmusclesarederivedfromeithersomitesorsomitomeres.Asomitomeresisastructure foundinthecephalicandoccipitalregionsthatresemblesimmaturesomites.Theseareof branchiomericoriginandarereferredtoasbranchiomeres.Somitesappearalongsideofthedeveloping spinalcordinthevariousbodyregions(seeabove). Myotomesdevelopfromsomites,andeachmyotomeiscomposedoftwodivisions,asmalldorsal, epaxialdivisionandalargerventral,hypaxialdivision.SmallDorsalEpaxial;LargerVentralHypaxial. Eachspinalnervedividesandsendsabranchtoeachdivision,thedorsalprimaryramustotheepaxial divisionandtheventralprimaryramustothehypaxialdivision.Eachdivisionofamyotomeformsa specificgroupofmuscles.

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Thisimageshowstherelationship ofthemyotomeandthe dermatomewithinthe dermomyotomefirst,thenofthe epimereandhypomeresecond. ThelargeImagebehindthetwo closeupsshowswhattheepimere andthehypomerewillbecome. Linkthesedevelopmentalstages andlocationswithyour SuperficialandDeepBackfrom anatomytodetermineinnervation.

Epimeres(myoblastsfromtheepaxialdivision;meresmeanscells;epimeanscomefromepaxial division)formthedeepdorsaltrunkmuscles(extensorsofthebackandvertebralcolumnandextensors ofthelumbarregion)andaresuppliedbydorsalprimaryramiofthecorrespondingspinalnerve. Hypomeres(myoblastsfromthehypaxialdivision;meresmeanscells;hypomeansfromhypaxial division)formalloftheremainingmusclesofthetrunkandsomelimbmusclesandaresuppliedby ventralprimaryramiofspinalnerves. Thehypomeresgiverisetoboththelateralandventralflexormusculature.Theventralmusculature splitsinto3separatelayers,whichcanbeidentifiedinthethoraxastheexternalintercostal,theinternal intercostal,andtheinnermostintercostalsorthetransversethoracismuscle.Intheabdominalwall, these3layersconsistoftheexternaloblique,theinternalobliqueandthetransverseabdominus muscle.Theintercostalsregaintheirsegmentedcharacterduetothepresenceoftheribs.Most muscleshowever,areformedbymyoblaststhathavemigratedandhavefusedwithothermyoblasts toformsheetsofmuscles.

Thisisacrosssectionoftheabdomen(likeaCT scan)showingthefatesoftheepimereandthe hypomeres,includingwhichmusclestheywill becomeandwhattheyareinnervatedby.This specificallyshowstheabdominalmusclesandwhere theycomefrom.

Branchiomeres(myoblastsfromthebranchialarches,whichdevelopintotheface,somethingyouhave notcoveredyet;meresmeanscells;branchiomeansfrombranchialarches)formthemusclesof masticationandfacialexpression,aswellascertainpharyngealandlaryngealmuscles;thesemuscles becomeinnervatedbythebranchialarchnerves:Thetrigeminal(V),facial(VII),glossopharyngeal |T 1 F o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

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(IX)andvagal(X).ThisisinHillsnotes,butyouwillnotgettocranialnerves,norfacialdevelopment untiltheendofanatomy.Therewasnogoodimageofthis. Mostofthelimbmusculaturedevelopsfrommigratingsomaticcells(epimericorhypomericcells),but somedevelopsinsitufromthemesenchymesurroundingthedevelopingbones.Somemigrationfrom epimeresandhypomeresdoesoccur. Originanddevelopmentofsmoothmuscle: SmoothmuscleoftheGItractisderivedfromthesplanchnicmesodermsurroundingtheendodermof theprimitivegutanditsoutgrowths(liver,gallbladder,pancreas).Somesmoothmuscle,specificallythat whichisfoundinthewallsofmanybloodvesselsandlymphaticchannels,isderivedfromsomatic mesoderm.Stillsomeothersmoothmuscles,likethatoftheoftheiris(sphincteranddilatorpupillae), aswellasthemyoepithelialcellsofthemammaryglands,arethoughttobederivedfrommesenchymal cellsofneuralcrest(ectoderm)origin. GI=SplanchinicMesoderm,BloodVessels=SomaticMesoderm,Iris=NeuralCrestEctoderm, Thetrainofeventsinmyoblastdevelopmentissomewhatdifferentfromthatseeninskeletalmuscle development,andnofusionofadjoiningmyoblastsoccurs.SmoothmusclesareNOTmultinucleated fibers(asyouwilllearnindetailinHisto/physio),sothereisnofusionofcells. Originanddevelopmentofcardiacmuscle: Cardiacmuscleoriginatesfromthesplanchnicmesodermsurroundingtheearlyendocardialhearttube (myoepicardialmantle).Thecardiogenicmyoblastsformthemyocardium.Thereisnofusionof myoblastsasisseeninthedevelopmentofskeletalmuscle(likesmoothmuscle,cardiacmuscleisnot multinucleated).Theindividualmyoblastsdifferentiateandgrow,addingtotheircomplementof myofibrils,andeventuallyadheretooneanotheratjunctionalinterfaces,whichultimatelybecomethe complexstructuresknownasintercalateddiscs.Atypicalcardiacmusclefibersthatmakeupthe Purkinjefibersoftheheart'sconductingsystemwillformlateintheembryonicperiod. III.LimbDevelopment UPPERLIMBappearsonday24assmallbulgesonthelateralbodywallatC5C8level,whilethe LOWERLIMBappearsatL3L5severaldaysafterthedevelopmentoftheupperlimb LimbMusculatureandDevelopmentCellularandMolecularAspects: TheLimbbudconsistsofamesenchymalcorecoveredoverbyanectodermalcap.TheLimbbudis inducedtoformbyadjacentsomites.Thedistalmarginoftheectodermalcapthickenstoformthe ApicalEctodermalRidge(AER).TheAERisinducedtoformbythemesodermalcore.Itthenactsbackon themesoderm.MesenchymeadjacenttoAERconsistsofundifferentiatedcellsthatareinducedbyAER todifferentiateintothemesenchymalmodel,bloodvessels,cartilage,andbonemodels.Sothe mesodermtellstheectodermtobecometheAER,thentheAERtellsthemesodermtobecomealimb. Thelimbscomefromthesomatopleuriclateralplatemesoderm,whichmigrateoutwards.Atthesame time,myotomesmigrateandinvadethemesoderm.Themesodermwillbethebone,thedermatome theskin,andthemyotomethemuscleofthedevelopinglimb.Mostofthissectionwasspedthrough, andHillwantedtofocusmoreonthemolecularbasisratherthanthedevelopmentofthelimbitself.

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Myotomemigratesand invadesmesoderm, generatingthebud

Overthecourseofweeks,the limbbudextends, differentiates,andgivesrise toahandplate,thento individualdigits.

Molecularbasisofpatternformation Thespatialorganizationofdifferentiatedcellsandtissuesaccountsforthemorphogenesisoftheorgans andbodyasawhole.ZoneofpolarizingActivity(ZPA)producesamorphogengradientthatcanbe interpretedbycellsinlimbbud.BecauseconcentrationwillbegreaterclosertotheZPAandlessfarther away,thegradationallowsforcontrolofgeneexpressionandthusdevelopment. EarlystudiessuggestedthatRetinoicAcidwasthemorphogenproducedbycellsintheZPA.The concentrationofRetinoicAcidis2.5timeshigherinZPAthanothersites.Thereisaconcentration gradientofRAfromapicaltodistal.WenowbelieveFGF8stimulatesSHHinZPA.Yes,itiscalledSonic HedgeHog.No,theywerenotSegafans,butratherthespinesonthebacksoforganismsofSHH knockoutsresembledahedgehog. Thisnextsectionisadipintobiochemistry,whereweexplorenuclearreceptors.Thisiskept intentionallybrief.CellsoflimbbudscontainRetinoicAcidReceptors(RAR).RARsaresteroidreceptors (opposedtoplasmamembranesurfacereceptors)andactasnucleartranscriptionfactors(actingand changingDNAdirectly)thatactivateorrepressthetranscriptionofspecificgenes.TotargetthatDNA, theremustbesteroidresponseelements,or,inthiscaseretinoicacidreceptorresponseelements, RAREs.SowhenRetinoicacidisproduced,itbindstoitsreceptor,whichthenbindsDNA,turningonor turningoffgeneexpression. Soimportantisthisconceptthatthereareafewexercisesonecando.IfyoutaketheZPAfromone embryoandputitonadevelopingembryo,yougetanotherlimb.Ifyouplaceabeadfullofretinoicacid insteadofthenewZPA,yougetanotherlimb.Theactualexperimentwasdonewithfingersanddigit number,shownonthenextpage.ButthegististhattheZPA,viaretinoicacid,istheinducerof segmentation. |T 1 F o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r
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ZPAtakenfromanotherembryoorabeadwith retinoicacidproducethesameresult

FGF8fromAERisalsoasteroidhormone,inducingtheexpressionofhomeoboxgenes(HOXgenes). Thesearemastergenethatregulatetheexpressionofothergenesbyproducingtranscriptionfactors. Hox4genesactivatedinacraniocaudalsequenceandarekeyinproximaldistaldifferentiation. RetinoicAcidinducesFGF9andFGF2expressionwhichinturnregulatetheexpressionofSHHgene andHOX4and7genescriticalforlimbpatterning. D.CONGENITALANAMALIESOFTHELIMB: Therearethreecategoriesoflimbdefects: (1.)reductiondefectsinwhichpartofalimb(meromelia)orandentirelimb(amelia)ismissing. (2.)duplicationdefectsinwhichtherearemorethanyoushouldhave(polydactylyisthepresenceof extradigitsandisthemostcommonexample). (3.)Dysplasiamalformationofthelimbincludesyndactyly(fusionofthedigits),andgigantism( excessivegrowthofthedigits)

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