LecLure 9

1 neuroembryology
O name and descrlbe Lhe sLrucLures ln Lhe nervous sysLem whlch develop from Lhe neural
Lube and neural cresL

neural Lube braln and splnal cord

neural cresL neurons ouLslde of Lhe CnS and cranlal and splnal nerves LhaL connecL
Lhe braln and Lhe splnal cord wlLh perlpheral sLrucLures

LcLoderm CnS neurons glla
LcLoderm
Surface ecLoderm
Lpldermls
Palr
nalls

neural cresL
nS
Schwann cells
SympaLheLlc nS
arasympaLheLlc
nS
Sensory neurons
Adrenal medulla
MelanocyLes
laclal carLllage
uenLlne of LeeLh

neural Lube
8raln
Splnal cord
MoLor neurons
8eLlna

Mesoderm muscle clrculaLory sysLem
Lndoderm dlgesLlve Lube resplraLory Lube

O Lxplaln Lhe role of bone morphogeneLlc proLeln (8M) ln ecLoderm dlfferenLlaLlon
lormaLlon of neural plaLe
8M suppresses neural dlfferenLlaLlon ln ecLodermal Llssue and
promoLes formaLlon of epldermal Llssue
Chordln and noggln proLelns from hensen's node block Lhe acLlon of
8M and allor for a selecLlon of ecLoderm cells Lo form neural plaLe
(chordln and noggln sLopplng 8M allows for neural dlfferenLlaLlon Lo
occur agaln and form neural Lube)

O 8eallze Lhe cllnlcal consequences of falled neural Lube closure (rosLral and caudal)
A fallure of Lube Lo close rosLrally leads Lo a anencephaly feLus lacks
neocorLex
lallure of Lube Lo close caudally leads Lo splna blflda (parL of Lhe
menlnges or splnal cord proLrudes Lhrough Lhe splnal column)

2 SegmenLaLlon
O ueflne homeoLlc (homeobox) genes (Pox famlly) Learn Lhe source and role of reLolnlc
acld ln Lhe dlfferenLlal expresslon of Lhese genes
PomeoLlc genes masLer genes" conLrolllng Lhe expresslon of many oLher genes
durlng developmenL CreaLe sLrucLures approprlaLe Lo a parLlcular anLerlorposLerlor
poslLlon ln Lhe verLebraLe embryo

A longlLudlnal gradlenL of reLlnolc acld deLermlnes Lhe paLLern of Pox gene expresslon
lL ls produced by Pensen's node 8A acLlvaLes LranscrlpLlon of Pox genes
ulffuslon of 8A from Lhe node esLabllshes a gradlenL along Lhe shorL lengLh of
Lhe embryo LhaL conLrlbuLes Lo Lhe orderly anLerlorposLerlor sequences of Pox
gene expresslon ln Lhe hlndbraln

O uescrlbe Lhe developmenL mechanlsms of Lhe hlghly segmenLed rhombencephalon
segmenLal boundarles are noL crossed by cells a form of comparLmenLallzaLlon Pox
genes creaLe proper anLerlorposLerlor orlenLed sLrucLures Sonlc hedgehog does
venLral and 8M does dorsal

O DndersLand Lhe source of sonlc hedgehog proLeln Lhe lnfluence of Lhls proLeln on Lhe
neural Lube and Lhe slgnlflcance of lLs lnLeracLlon wlLh 8M
Sonlc hedgehog ls synLheslzed by Lhe noLochord (and laLer by Lhe floor plaLe) Plgh
levels are found on Lhe surface of Lhe noLochord whlch lnduces cells of Lhe neural Lube
Lo become floor plaLe cells CradlenL on Lhe floor plaLe lnduces formaLlon of moLor
neurons Mnspeclflc genes eg ChA1 lL ls a venLrallzlng slgnal
8M ls a dorsallzlng slgnal lL speclfles cells ln Lhe dorsal horn and neural cresL cells lL
lnhlblLs spread of venLrallzlng slgnals from noLochord lnLo dorsal reglons

O AppreclaLe Lhe lmpllcaLlons of experlmenLs whlch over express Lhe eyeless" gene ln
drosophlla
ulsplacemenL or muLaLlons of Lhe hox gene speclflcally Lhe eyeless" gene causes eyes
Lo develop where Lhe gene was placed

O Learn cerebral corLex anomalles assoclaLed wlLh defecLs ln Lhe genes emx and oLx
CeneLlc abnormallLles of emx schlzencephaly
CeneLlc abnormallLles of oLx epllepsy

O ueflne prlmary and secondary veslcles and assoclaLed nervous sysLem sLrucLures

3 Cell prollferaLlon
O ldenLlfy neuronal cellular acLlvlLy aL Lhe venLrlcular and plal surfaces durlng
developmenL
1he cell nucleus mlgraLes Lo Lhe Lube's lnner or venLrlcular surface Lhe plal end of Lhe
cell deLaches Lhe cell dlvldes and Lhe nuclel of Lhe daughLers mlgraLe Loward Lhe ouLer
surface as Lhe cells reaLLach Lo LhaL surface unA synLhesls (S phase) occuers near Lhe
plal surface MlLosls (cell dlvlslon) occurs aL Lhe venLral surface

O ueflne Lhe marglnal and venLrlcular zones ln Lhe Lelecephallc veslcle
lal ouLer surface ls Lhe marglnal zone Lhls ls where unA repllcaLlon occurs 1he
venLrlcular zone ls Lhe lnner zone where cell dlvlslon occurs

4 Cell mlgraLlon
O ueflne and undersLand Lhe role of radlal gllal cells
8adlal gllal are neurons whlch malnLaln Lhelr conLacLs wlLh boLh Lhe venLrlcular and plal
surfaces of Lhe neural Lube ueveloplng neurons move along Lhls scaffoldlng of radlal
gllal cells Lo reach Lhelr approprlaLe poslLlons ln Lhe corLex

O DndersLand whaL ls meanL by Lhe layers of corLex developlng ln an lnsldeouL" fashlon
?ounger neurons Lyplcally mlgraLe pasL Lhe older ones 1he newer cells are on Lhe
ouLslde and develop lasL whlle Lhe older cells developlng early are found on Lhe lnslde

O AppreclaLe Lhe lmporLance of Lhe ca[alreLzlus cells and Lhe reeler gene wlLh regard Lo
cellular mlgraLlon
ln reeler mlce Lhe reeler neurons fall Lo mlgraLe pasL one anoLher ln Lhe developlng
corLex 1helr relaLlve posLlons ln Lhe adulL are lnverLed neurons born early end up ln
Lhe mosL superflclal layers whereas neurons born laLer end up ln deeper layers 1he
producL of Lhe reeler gene ls a large exLracellular maLrlx glycoproLeln called reelln lL ls
noL expressed ln Lhe corLlcal cells LhaL fall Lo mlgraLe properly buL raLher ln ca[alreLzlus
cells ln Lhe marglnal zone of Lhe corLex 1he ca[alreLzlus release Lhe reeler 1here ls a
problem wlLh Lhese cells reeler mlce

O DndersLand how Cn8P produclng cells provlde one excepLlon Lo Lhe general prlnclple
LhaL radlal gllal cells provlde guldance for mlgraLlon
neurons expresslng Cn8P mlgraLe lnLo Lhe CnS ln Lhe perlpheral nS neural cresL cells
mlgraLe along paLhways LhaL lack boLh axon LracLs and organlzed gllal sLrucLured Cells
of Lhe neural cresL mlgraLe along paLhways marked by lamlnln and oLher key molecular
componenLs of Lhe exLracellular maLrlx

3 Cell maLuraLlon and commlLmenL
O DndersLand how Lhe neuron's envlronmenL lnfluences lLs commlLmenL Lo funcLlon
Cnce a cell has mlgraLed lLs envlronmenL can lnfluence lLs maLuraLlon lor example for
cells of Lhe neural cresL LhaL glve rlse Lo sensory and auLonomlc ganglla Lhe Lype of
LransmlLLer released depends upon Lhe slLuaLlon where Lhe neurons come Lo resL and
whlch LargeLs Lhey maLched wlLh

O AppreclaLe Lhe role of neuronal locaLlon ln deLermlnlng Lhe speclflc neuroLransmlLLer
released by speclflc cells
neural cells can change Lhelr phenoLype when moved Lo a locaLlon of a dlfferenL
neuroLransmlLLer le cells LhaL would have released Ach when LransplanLed Lo a
sympaLheLlc slLe wlll begln Lo release caLecholamlnes

O Learn role of leukemla lnhlblLory facLor as an example of local pepLlde lnfluences on
neuronal cell phenoLypes
lL ls secreLed by ecLodermal cells lL caused chollngerglc dlfferenLlaLlon of adrenerglc
sympaLheLlc neurons
ln vlLro exp noradrenerglc nCC coculLures wlLh cardlac muscle + Lll released by muscle
cells nCC becomlng chollnerglc

O DndersLand Lhe role of M22 proLeln ln myellnaLlon of perlpheral nerves
M22 ls essenLlal for Lhe layers of Lhe Schwann cell membranes Lo wrap and seal
Lhemselves around developlng axons lL ls reallzed by Schwann cells ln Llssue culLure
Schwann cells on Lhelr own make M22 buL break lL down lnsLead of leLLlng lL become
LransporLed ln Lhe membranes Cnce neurons are puL lnLo Lhe culLure wlLh Lhe Schwann
cells Lhey no longer break lL down lnsLead lL ls expressed ln Lhelr membranes whlch
fuse Lo form myelln

O Lxplaln Lhe relevance of Schwanncell neuron lnLeracLlons Lo Lhe approprlaLe
expresslon of M22


O Learn how experlmenLs wlLh Lhe Lrembler" mouse (wlLh geneLlc myellnaLlon
deflclencles) lllusLraLe Lhe lmporLance of Schwann cell's role
Myelln Lhe Lrembler" mlce falls Lo form properly Powever lf a lengLh of Lhe sclaLlc
nerve of a normal mouse ls cuL ouL and grafLed lnLo Lhe sclaLlc nerve of Lhe Lrembler
mouse Lhe regeneraLlng Lrembler axons LhaL encounLer normal Schwann cells from Lhe
grafL do become myellnaLed normally Pence Lhe defecL ls noL ln Lhe axons buL ln Lhe
Schwann cells of Lhe Lrembler

O AssoclaLe knowledge of M22 proLeln wlLh CharcoL Marle 1ooLh dlsease
CharcoL Marle 1ooLh dlease Lhe M22 ls noL normal perlpheral myelln falls Lo form
properly slngle aa subsLlLuLlon ls Lhe cause of defecL

O Learn Lhe role of lamlnln ln axonal ouLgrowLh
lL ls synLheslzed by Schwann cells parLlcularly afLer an ln[ury lL ls presenL along
paLhways of growlng axons Axons follow Lhese paLhways as Lhey exLend Lhelr processes
ln Lhe developlng nervous sysLem lL promoLes neurlLe ouLgrowLh lnLegrln molecules
on Lhe growLh cone blnd Lo Lhe lamlnln and pull Lhemselves along Lhe paLhway

O 8e aware of Lhe dlffuslble subsLance neLrln" and lLs lnfluence on axon growLh wlLh
speclflc regard Lo moLor versus sensory neurons
neLrln ls a long range aLLracLanL uCC ls lL's recepLor
nrCAM ls a shorL range aLLracLanL 1AC1 ls lL's recepLor 8lndlng axons remaln
lpsllaLeral
SllL ls a shorL range repellenL 8obo ls lL's recepLor
SllL+neLrln 1 are long range repellenLs DnC3 ls a recepLor LhaL repels

WlLh moLor neurons before lnnervaLlons skeleLal muscle cells have Ach recepLors
scaLLered over Lhelr enLlre surface AfLer lnnvervaLlon recepLors aggregaLe aL Lhe
endplaLe ln response Lo a parLlcular proLeln agrln released by Lhe nerve 8ecepLors
become hlghly concenLraLed aL Lhe endplaLe SenslLlvlLy ouLslde Lhe endplaLe
dlsappears

Llgand 8ecepLor LffecL
nrCAM shorL range
(conLacL medlaLed)
1AC1 ALLracLlon

SllL (shorL range) 8obo 8epulslon
Lphrlns (long range) Lph8ecepLors 8epulslon
neLrln (longrange
dlffuslble llgand)
uCC ALLracLlon
neLrln long rangedlffuslble DnC3 8epulslonMoLor nS


6 Cell survlval and deaLh
O DndersLand Lhe baslc mechanlsms LhaL explaln Lhe acLlons of nerve growLh facLor
lncludlng Lyroslne recepLor klnase acLlvlLy
nerve growLh facLor causes Lhe ouLgrowLh of neurlLes ln cell culLure nCl regulaLes Lhe
synLhesls of norepl by lnduclng Lwo enzymes requlred for lLs synLhesls Lyroslne
hydroxylase and dopamlne bhydroxylase
nCl musL be Laken up lnLo nerve Lermlnals and acLlvely LransporLed back Lo Lhe soma
AfLer Lhe blndlng of neuroLrophlns Lo Lhelr hlgh afflnlLy recepLors ls an lncrease ln
Lyroslne phosphorylaLlon of Lhe recepLors Lhemselves 1hls acLlvaLes Lhree lnLracellular
slgnallng paLhways phosphollpase C phosphaLldyllnoslLol3klnase and Lhe MA klnase
cascade

O Lxplaln Lhe role of nCl for sympaLheLlc and dorsal rooL gangllon sLrucLures
When anLlserum Lo nCl was ln[ecLed lnLo newborn mlce Lhelr sympaLheLlc nervous
sysLem falled Lo develop 1he parasympaLheLlc nervous sysLem was noL affecLed and
Lhe dorsal rooL ganglla were only sllghLly smaller Lhan normal 1he anlmals llved
normally buL responded poorly Lo sLress condlLlons

O ldenLlfy Lhe lmporLance of Lhe neuroLrophln famlly of growLh facLors
neuroLrophlns
8ralnderlved neuroLrophlc facLor (8unl)
n13 n14/3 n16 (8unlrelaLed)
4 rollferaLlon dlfferenLlaLlon survlval
llrsL produced by axons and mesenchymal Llssue laLer by LargeL cells
LaLer neurons epress nCl recepLors and become dependenL on LargeL
nCl for survlval

O ueflne apopLosls and lLs lmporLance ln neurodevelopmenL
Cell deaLh (apopLosls) seems Lo provlde a numerlcal maLchlng beLween neurons and
Lhelr LargeLs for removal of LargeLs lncreases moLor neuron deaLh and dupllcaLlon of
LargeL saves cells

O AppreclaLe how cell deaLh appears Lo be cruclal for approprlaLe maLchlng of moLor
neurons and skeleLal muscle LargeLs
A compeLlLlon apparenLly arlses beLween Lhose moLorneurons LhaL have survlved Lhe
perlod of cell deaLh each resLrlcLlng whlle sLrengLhenlng lLs Lermlnals so as Lo produce
slngly lnnervaLed muscle flbers
1 Muscle flber acLlvlLy promoLes slngle lnnervaLlon lnacLlvlLy or denervaLlon
promoLe polyneural lnnervaLlons
2 1rophlc facLors produced by muscle and glla nCl Laken by reLrograde axon
LransporL

7 SpeclflclLy of synapLlc connecLlons
O DndersLand Lhe speclflclLy example elucldaLed ln Lhe frog's reLlna Lo LecLum connecLlons
Axons from gangllon cells locaLed ln Lhe Lemporal parL of Lhe reLlna
selecLlvely lnnervaLe neurons ln anLerlor LecLum
Axons from gangllon cells ln Lhe Lemporal reLlna pro[ecL Lo anLerlor
LecLum
Axons from gangllon cells ln nasal reLlna pro[ecL Lo posLerlor LecLum
1emporal cells are repelled by Lph (ephrln) nasal cells are noL repelled
because Lhey do noL express Lhe approprlaLe recepLor
Lphrln ls ln hlghesL concenLraLlon ln posLerlor LecLum (where Lhere are
no Lemporal ganglla)
1emporal AnLerlor
nasal osLerlor

O Learn Lhe role of Lph (ephrln) famlly of recepLor Lyroslne klnases
1he Lph famlly of recepLor Lyroslne klnases and Lhelr llgands are responslble for Lhls
repulslve lnLeracLlon


O AppreclaLe how llgands for ephrln recepLors (ephrln A2 and A3) are expressed
dlfferenLlally wlLh regard Lo Llme and locaLlon (LecLum concenLraLlon gradlenL)
1helr concenLraLlon ls hlghesL ln Lhe posLerlor LecLum and lowesL ln Lhe anLerlor
LecLum Slmllarlly eph recepLors are presenL ln hlgher concenLraLlons on Lhe Lemporally
locaLed gangllon cells (whlch cannoL enLer posLerlor LecLum) Lhan on nasally locaLed
gangllon cells (whlch do grow lnLo posLerlor LecLum slnce Lhey are noL lnhlblLed)Lph A2
and A3 added Lo Lhe medlum cause growLh cone Lo deLach from subsLraLe and reLracL

O 8eallze Lhe llmlLaLlons of knowledge regardlng synapLlc speclflclLy
O DndersLand how a skeleLal muscle moLor end plaLe sLarLs off by belng lnnervaLed by 3 or
6 moLor axons all of whlch reLracL subsequenLly leavlng [usL one

O ueflne Lhe crlLlcal perlod ln relaLlon Lo vlsual pro[ecLlons from Lhe laLeral genlculaLe
nucleus Lo Lhe vlsual (sLrlaLe) corLex
1he Llme of plasLlclLy ln Lhe young anlmal durlng whlch cerLaln aspecLs of vlslon can be
alLered by acLlvlLy (or lnacLlvlLy) and Lhose changes Lhen reversed before Lhey become
permanenL ln Lhe adulL ls called a crlLlcal perlod
1he crlLlcal perlod ln humans ls 3 monLhs uefecLs are besL correcLed durlng flrsL weeks
of developmenL

O Learn Lhe dlfference ln changes Lo ocular domlnance columns afLer monocular
deprlvaLlon before and afLer Lhe crlLlcal perlods
1he wldLh of Lhe column borders changes afLer monocular deprlvaLlon lf lL occurs before
Lhe crlLlcal perlod lf monocular deprlvaLlon occurs afLer Lhe crlLlcal perlod Lhere are no
conquences Lo Lhe wldLhs of Lhe columns 1he losL eye pro[ecLs shrlnk and Lhe
sLlmulaLed eye ganglla columns expand and reLaln more cells

O lnLerpreL hlsLograms demonsLraLlng shlfLs ln ocular domlnance durlng monocular
deprlvaLlon ln Lhe crlLlcal perlod
O DndersLand how genlculaLe axon reLracLlon occurs and know Lhe effecL on Lhls process
when monocular bllndness occurs durlng Lhe crlLlcal perlod