FMS II DEv of Limb.ppt
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DEVELOPMENT OF LIMB
Dr Anggraini Barlian
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Classification of mesoderm : Notochord& a(ial !esoder!
in ad"lt s"bstit"ted b# col"!na vertebrate
schleroto!e ro! so!ite
+o!ite & $ara(ial !esoder!- Der!ato!eDer!is- M#oto!e s.eletal !"scle- +chleroto!evertebrae/ ribs
Mesoder! inter!ediate & 0rogenital s#ste! Mesoder! lateral &
- !esoder! s$lancnic & circ"lator# s#ste!- !esoder! so!atic & li!bs
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Stages development ofsomites:
A. Mesoderm cells arearranged around a
small cavity
B. Cells of ventral &medial walls ofsomites lose theirepithelial arrangement
& migrates notochordsclerotomeCells at dorsolateralmigrate limb &body wall
musculature.Dorsomedial cellsmigrate myotome
C.Myotome continueto etend
D. Dermatome
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Expression patterns of genes that regulates somite differentiation. Sonichedgehog (Shh),secreted by notochord floor plate of neural tube ventralpart of somite form sclerotome expressed !"#$
control chondrogenesis vertebral formation. %nt protein
activate !"#&
demarcates dermomyotome.%nt prot dorsomedial portion of somite form epaxial muscle expressmuscle specific gene 'yf. 'iddorsal portion of somite
dermis byneurotropin &(*+&)expressed by dorsal neural tube. ypaxial musculature isderived from the dorsolateral portion of somite under activating %nt prot -'!+ rot to ether activate ' oDex ression
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/0'- -1D 234'"*03
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!"#$"#%%
Li!b B"d For!ation
The distal ti$ o the li!b b"d is covered %ith a transient
str"ct"re .no%n as the apical ectodermal ridge ("E4)1Li!b o"tgro%th is de$endent "$on interactions bet%eenthe AE2 and the "nderl#ing !esoder!1
I the AE2 is re!oved/ the !esoder! sto$s dividing1
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!"#$"#%%
Li!b Develo$!ent
I a s"$ern"!erar# AE2 is grated adjacent to adevelo$ing li!b/ a s"$ern"!erar# li!b res"lts1
Pros$ective li!b !esoder! grated "nder lan.ectoder! %ill $ro!ote or!ation o an AE2 and as"$ern"!erar# li!b1
I li!b b"d !esoder! is re!oved ro! an earl#li!b b"d/ the AE2 regresses and the !esoder!ceases $rolieration1
Thereore/ li!b o"tgro%th involves reci$rocalinteractions bet%een the AE2 and "nderl#ing!esoder!1
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3hat 4ontrols Establish!ent o Li!b A(es5
The li!b has three a(es& Pro(i!o*distal6 Anterior*$osterior and Dorsal*ventral1
!roximo+distal
2e!oval o the AE2 at $rogressivel# later stagesres"lts in a tr"ncated li!b %ith $rogressivel# !oredistal ele!ents1 Th"s/ these ele!ents are laid do%n ina $ro(i!al*to*distal direction1
The AE2 does not reg"late P*D $olarit#1 Fates o cellsare deter!ined b# the length o ti!e the# s$end in theprogress 5one1 Those residing there the longestbeco!e the !ost distal ele!ents1
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!"#$"#%%
Anterior*Posterior A(is
This a(is is deter!ined b# the 5one ofpolari5ing activity (6!")/ %hich is located at
the j"nction bet%een the li!b b"d and thebod# %all1
7rats o the 8PA to the anterior !argin o a
host li!b b"d ca"ses d"$lication o digits in!irror*i!age s#!!etr#1
A di"sible !or$hogen 9retinoic acid5: is
released ro! the 8PA1
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3hich a(is or!s irst5
;1 anterior)$osterior 9;stto
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0$$er Li!b
+ca$"la
,"!er"s
2adi"s/ "lna
4ar$als Digits
- Metacar$als
- Phalanges
Lo%er Li!b
Pelvis
Fe!"r
Tibia/ ib"la
Tarsals Digits
- Metatarsals
- Phalanges
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+ca$"la
,"!er"s
2adi"s/ "lna
4ar$als
Digits
- Metacar$als
- Phalanges
0$$er Li!b
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%hy Study /imb
Development7 F"nda!ental 0nderstanding o the
$rocess
4linical relevance- +o!e statistics&
oFre?"enc# o abnor!alit# de$ends on severit#
oD"$lication o digits is airl# co!!on at @; in> births
oMajor ail"res o or!ation is less co!!on/ at@ ; in ;/ births
9Indiana ,and 4enter:
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o8 do these abnormalities
arise7
*4319 0'!43!E4
DEE/3!'E*;;;
The goal of limb development research is to
understand how cartilage, muscle and tendonsare formed in the right place and how they
make the right connections with each other to
form a normal functional limb
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/imb Development is " !art
of 3rganogenesis The $rocess o organogenesis involves
"sing the basic bod# $lan 9organiede!br#o: to develo$ s$eciic organs 9li!bs/
heart/ e#es: in s$eciic regions that leadsto the "ll# "nctional organis!/ ca$able oinde$endent s"rvival- Involves& $attern or!ation/ s$eciication o
$ositional inor!ation/ ind"ction/!or$hogenesis/ and cell"lar dierentiation
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o8 are these processes
involved7 Pattern or!ationdirects cell identit# and leads
to ordered s$atial $attern o cell activit#
Positional inor!ationdirects %here organs%ill or!
Ind"ctiondirection o s$eciic cell ate
Mor$hogenesischanging the or! o cells
Dierentiation ac?"ire "nctional and str"ct"ralidentit# distinct ro! their s"rro"nding cells
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'odel System rdda#
ater la#ing
The li!b develo$
ro! li!b b"ds on thebod# %all o the
e!br#o
De elopment of the Chic= /imb
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Development of the Chic= /imb
00
Development of the Chic= /imb
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Development of the Chic= /imb
000As the limb bid grows outward, cells in the progress zone
proliferate and acquire a positional value
When cells leave the progress zone, cartilage may begin to
differentiate, and other elements gain their positional
information
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Embryonic Chic= %ing (day
$>)
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%hat Directs /imb Development7
The API4AL E4TODE2MAL 2ID7E 9AE2: is
res$onsible or the $ro(i!o*distal $atterning o theli!b/ %hich occ"rs over ti!e thro"gh the $rogress
one
+ignals are sent both ro! the AE2 to the $rogress
one/ and ro! the $rogress one to the AE2
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%hat Directs /imb
Development7(cont?d) The 8ONE OF POLA2I8IN7 A4TIVITC
98PA: is res$onsible or antero*$osterior
$atterning o the li!b The E4TODE2M controls $atterning
along the dorso*ventral a(is
Differences in the activation of genesthat control the interpretation ofpositional information is responsiblefor development of different limb
structures (i.e. upper or lo8er)
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3hat Molec"les Direct Li!b
Develo$!ent5 Sonic Hedgehog (Shh)
- The Shhgene encodesind"ctive signaling!olec"les that "nction
d"ring e!br#ogenesis- Involved in establishing
cell ates
- e# signal in $atterning
o the antero*$osteriorli!b a(is
-Alx-4re$resses Shhe($ression
Fibroblast GrowthFactor 4 (FGF-4)- Me!ber o F7F a!il#- Mesoder!al cell
sti!"lator and directsdevelo$!entalsignaling
- FGF-4*)* die on E
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!"#$"#%%
2etinoic Acid & A Develo$!ental
Mor$hogen
2etinoic acid is the active or! o Vita!in A
Both e(cess retinoic acid and vita!in A
deicienc# each aect let*right s#!!etr#
9e1g1/ abnor!al or!ation o the !a!!alian
heart: thro"gh alterations in gene e($ression1
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!"#$"#%%
4ell Death and Digit For!ation
'ithout apoptosis( the )ngers would be webbed.:syndactyly
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Li!b !alor!ation
*hese are clenched hands resulting
from camptodactyly +)ngers bentover, and clinodactyly +)ngersinclined to one side or the other,. *hisparticular appearance is verysuggestive of trisomy -.
Deformation from constraint witholigohydramnios in utero can result inthe appearance of the club feet
+varus deformity, seen here. *he feetare turned inward.
E l f b li b f
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Eample of abnormalityabsent of
hands !" legs#
!amelia$ phocomelia#caused by
thalidomide !anti%vomiting#
Syndactyly represents fusion of two ormore digits. /t can be an isolated)nding or part of syndromes thatde)ne patterns of anomalies. Most ofthese syndromes do not have aspeci)c genetic defect yet de)ned(though some do. Seen above are thedigits of the hand fused together.Below the foot has rudimentar
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Sirenomelia+caudaldysgenesis,gastrulationdisruption. 0oss ofmesoderm in the
lumbosacral region hasresulted in fusion of limb
*his is sirenomelia. *he term comes from 1siren1or 1mermaid1 because of the characteristic fusion
of the lower etremities that results from a failurein the development of a normal vascular supplyto lower etremities from the lower aorta inutero.
2eg"lative
abilit# o Li!bield
%h t th
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%hat are these
abnormalities7
&olydactyly ' the
duplication of a digit
Caution: aspirin2 streptomycin
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Caution: aspirin2 streptomycin+deafness,2 antidepressant +limbdeformities,2 tetracyclin +bone andtooth anomalies, etcCocaine( 0SD( 3C3 +C4S( limbabnormalities( hypoia,
Child with unilateral amelia
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'"/234'"*03 0 C4"0"/ DEE/3!'E*
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E4*E-4" C3/1' DEE/3!'E*
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Develo$!ent o vertebrae
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Develo$!ent o vertebrae
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