BASES MOLECULARES DEL DESARROLLO EMBRIONARIO

Lagman 2010
Estructura del ADN
La cromatina es: ADN + protenas
Esta !orma"a por n#c$eosomas% E$ n#c$eosoma est& !orma"o por #n oct&mero "e
protenas 'istonas + 1(0 pares "e )ases%
Los n#c$eosomas est&n #ni"os por ADN * otras protenas 'istonas $$ama"as +1
E$ ADN est& enro$$a"o, as enro$$a"o no se p#e"e transcri)ir, se $$ama 'eterocromatina%
E$ ADN "esenro$$a"o se $$ama e#cromatina
Genes
Un gen est& comp#esto por e-ones .se sinteti/an $as protenas0 e intrones !orma"os por
so$o ADN 1#e no !orma protenas%
Regi2n promotora: sitio "on"e se #ne $a ARN po$imerasa
3#nto "e inicio "e $a transcripci2n
3#nto "e inicio "e $a tra"#cci2n: "on"e se #)ica e$ primer amino&ci"o "e $a protena
Co"2n "e para"a "e $a tra"#cci2n
Regi2n 45: $#gar "e inserci2n "e $a po$i .A0% s# !#nci2n es esta)i$i/ar e$ ARN * $e
permite sa$ir "e$ n6c$eo
7ranscripci2n: proce"e "e$ e-tremo 85'acia e$ e-tremo 49
Regi2n "on"e se #ne $a ARN po$imerasa
Contiene $a porci2n $$ama"a 7A7A
Ca:a 7A7A
3ara po"er #nir $a ARN po$imerasa a esta /ona se re1#iere "e protenas $$ama"as
;<actores "e transcripci2n=%
Los <7 tienen #n "ominio espec!ico para #nirse a$ ADN, tienen #n "ominio "e
transacti>aci2n .1#e acti>a o in'i)e $a transcripci2n "e$ gen0
Como res#$ta"o e$ ADN se "esenro$$a
3otencia"ores
E$ementos reg#$a"ores
Resi"en en c#a$1#ier parte "e $a mo$?c#$a "e ADN
Los potencia"ores se #nen a !actor "e transcripci2n, esto para reg#$ar $a
>e$oci"a" * e!iciencia "e $a e-presi2n "e$ gen%
+a* "i!erentes potencia"ores "e$ mismo gen en "i!erentes te:i"os% 3or e:emp$o
3A@A #n !actor "e transcripci2n tiene 4 potencia"ores "istintos: en e$ p&ncreas
#n potencia"or, en e$ o:o #no "istinto, en e$ t#)o ne#ra$ otro "istinto
Los $$ama"os si$encia"ores son potencia"ores 1#e in'i)en $a transcripci2n%
Un potencia"or acti>a #n gen * si$encia a otro%
ARN n#c$ear: es m&s $argo, contiene intrones
Desenpa$me: se e$iminan intrones%
Empa$me a$ternati>o: se sinteti/an "i!erentes protenas a partir "e #n mismo gen a$
e$iminar "i!erentes intrones, $os e-ones se empa$man "e "i!erente manera% Esto $o 'acen
$os enpa$mosomas 1#e son comp$e:os ARN B protena%
Iso!ormas "e empa$me: protenas 1#e "eri>an "e #n mismo gen% E:emp$o iso!ormas "e$
gen C71%
Una >e/ !orma"as $as protenas a s# >e/ p#e"en ser mo"i!ica"as * se a$tera s# !#nci2n,
son mo"i!icaciones postrans"#cciona$es%
<actores "e seDa$i/aci2n par&crinos
Los !actores "e crecimiento * "i!erenciaci2n son ( !ami$ias
Estas se #san en to"o e$ reino anima$
1E <F<
2E 3rotenas CN7
4E <ami$ia +e"ge'og
(E <ami$ia "e$ !actor "e trans!ormaci2n "e crecimiento )eta
1E <actores "e crecimiento "e $os !i)ro)$astos
7ienen este nom)re por1#e estim#$an e$ crecimiento "e $os !i)ro)$astos en
c#$ti>os
+a* "os "ocenas "e genes <F<
Acti>an cinasas receptoras "e tirosina, $o 'acen >a #n receptor: <F<<R
Acti>an "i>ersas >as "e seDa$i/aci2n como angiog?nesis, crecimiento "e $os
a-ones * "i!erenciaci2n "e$ meso"ermo
2E 3rotenas 'e"ge'og
Se $$aman as por1#e co"i!ican #n patr2n "e p#as en $as patas "e Drosop'i$a 1#e
rec#er"a $a !orma "e #n eri/o%
+a* 4 genes 'e"ge'og
Desert
In"ian
Sonic 'e"ge'og
S# receptor es $$ama"o 3atc'e" 1#e se #ne a $a protena $$ama"a Smoot'ene"%
La protena Smoot'ene" trans"#ce $a seDa$ "e 'e"ge'og, pero est& in'i)i"a por
e$ 3atc'e" 'asta 1#e $a protena 'e"ge'og se #ne a s# receptor%
La !#nci2n "e 'e"ge'og es p#es "esin'i)ir #n trans"#ctor 1#e norma$mente
estara acti>o%
4E 3rotenas CN7
Como mnimo e-isten 18 genes CN7 "istintos%
S#s Receptores pertenecen a $a !ami$ia "e protenas !ri//$e"% .risa"o0
3articipan en $a reg#$aci2n "e$ "iseDo "e $as e-tremi"a"es, e$ "esarro$$o "e$
mesenc?!a$o * a$g#nos aspectos "e $a "i!erenciaci2n "e $os somitas * "e $as
estr#ct#ras #rogenita$es%
(E La s#per!ami$ia "e$ !actor "e trans!ormaci2n "e$ crecimiento )eta
Est& !orma"a por m&s "e 40 miem)ros, entre $os c#a$es se enc#entran:
<actores )eta "e trans!ormaci2n "e$ crecimiento
Las protenas mor!ogen?ticas 2seas
La !ami$ia "e $a acti>ina
E$ !actor in'i)i"or "e M#$$er
Otros
Son importantes en $a !ormaci2n "e $a matri/ e-trace$#$ar, para $as
rami!icaciones epite$ia$es 1#e tienen $#gar "#rante $a !ormaci2n "e $os p#$mones,
e$ riD2n * $as g$&n"#$as sa$i>ares%
Moore 200G
Este conocimiento proce"e "e est#"ios en otros organismos como Drosop'i$a .mosca "e
$a !r#ta0 * ratones%
La interacci2n "e $os te:i"os cercanos "#rante e$ "esarro$$o es #n as#nto rec#rrente en $a
em)rio$oga% Uno se $$ama in"#ctor% D#rante e$ "esarro$$o oc#$ar $a >esc#$a 2ptica
in"#ce e$ "esarro$$o "e$ crista$ino% C#an"o !a$ta $a >esc#$a 2ptica no se "esarro$$a e$
crista$ino%
E$ mecanismo "e trans!erencia "e $a seDa$ se 'ace me"iante #na mo$?c#$a "i!#si)$e,
como $a pro"#ci"a por e$ gen "e$ eri/o s2nico .Sonic 'e"ge'og0, 1#e pasa "e$ in"#ctor
a$ te:i"o reacti>o%
La seDa$ se tra"#ce en #n mensa:e intrace$#$ar 1#e mo"i!ica $a acti>i"a" gen?tica "e $as
c?$#$as respon"e"oras%
Desp#?s "e $a in"#cci2n "e$ crista$ino por $a >esc#$a 2ptica, e$ crista$ino in"#ce e$
"esarro$$o "e $a cornea a partir "e$ ecto"ermo s#per!icia$%
3ara po"er respon"er a$ estm#$o in"#ctor, $as c?$#$as "e$ sistema reacti>o "e)en
e-presar e$ receptor a"ec#a"o para $a mo$?c#$a seDa$i/a"ora espec!ica, $os e$ementos "e
$a >a intrace$#$ar trans"#ctora "e $a seDa$ concreta * $os !actores "e transcripci2n 1#e
me"ian en "ic'a resp#esta%
3ara 1#e e$ proceso se $$e>e a ca)o se re1#iere contacto estrec'o entre $os te:i"os
in>o$#cra"os, si est&n m#* separa"os e$ proceso no oc#rre%
Car$son 2008
E$ mismo gen p#e"e act#ar en pero"os "istintos * en $a !ormaci2n "e "i!erente 2rgano%
As se re"#ce e$ n6mero "e mo$?c#$as necesarias para e$ contro$ "e$ "esarro$$o%
Esta &rea es "e m#c'o inter?s en $a in>estigaci2n onco$2gica%
Ca"a >e/ e-isten m&s pr#e)as "e 1#e e$ p$an "e "esarro$$o "e $os em)riones "e
mam!eros est& contro$a"o por m#c'os "e $os mismos genes 1#e 'an si"o i"enti!ica"os
en Drosop'i$a%
Las molculas que participan en el desarrollo se pueden agrupar en:
I- Factores de transcripcin
II- Molculas de sealiacin
III- !eceptores
I"- #ransduccin de la seal
I"- Acido retinoico
I"- Molculas de ad$esin
I- FA%#&!E' DE #!AN'%!I(%I&N: estos son protenas con "ominios 1#e se #nen
a$ ADN "e genes espec!icos% A"em&s poseen #na regi2n 1#e interact6a con $a
po$imerasa II "e$ ARN, o con otros !actores "e transcripci2n , as se reg#$a $a canti"a"
"e ARN 1#e pro"#ce e$ gen% A$g#nos "e e$$os son genera$es es "ecir 1#e e-isten en casi
to"as $as c?$#$as "e$ organismo, otros son espec!icos "e ciertos tipos ce$#$ares o "e
cierta !ase "e$ "esarro$$o%
Mechanism
Transcription factors bind to either enhancer or promoter regions of DNA adjacent to the genes
that they regulate. Depending on the transcription factor, the transcription of the adjacent gene
is either up- or down-regulated. Transcription factors use a variety of mechanisms for the
regulation of gene expression.
!"#
These mechanisms include$

stabili%e or bloc& the binding of 'NA polymerase to DNA

cataly%e the acetylation or deacetylation of histone proteins. The transcription factor can
either do this directly or recruit other proteins with this catalytic activity. (any
transcription factors use one or the other of two opposing mechanisms to regulate
transcription$
!)#

histone acetyltransferase *+AT, activity - acetylates histone proteins, which wea&ens

the association of DNA with histones, which ma&e the DNA more accessible to
transcription, thereby up-regulating transcription

histone deacetylase *+DA., activity - deacetylates histone proteins, which strengthens

the association of DNA with histones, which ma&e the DNA less accessible to
transcription, thereby down-regulating transcription

recruit coactivator or corepressor proteins to the transcription factor DNA complex

!/#
Los )actores de transcripcin son:
1E Genes que contienen $omeoca*a
7oma"o "e Moore octa>a e"ici2n
Las protenas pro"#ci"as contienen #n 'omeo"ominio a$tamente conser>a"o%
+omeobox genes are critical in the establishment of body axes during embryogenesis.
A- Genes +&,
7o"os $os genes +O@ contienen #na sec#encia "e 1G0 pares "e )ases, a esto se
$e "enomina $omeoca*a, .'omeosec#encia0, 1#e co"i!ica #n $omeodominio "e
A0 amino&ci"os !orma"o por tres '?$ices a$!a% La tercera '?$ice se #ne a sitios
ADN 1#e contienen #no o m&s moti>os "e #ni2n tetran#c$e2ti"o 7AA7HA77A en
$os promotores "e $os genes "iana%
La protena pro"#ci"a contiene #n 'omeo"ominio constit#i"o por A0
amino&ci"os, 1#e es "e$ tipo '?$ice B $a/o B '?$ice%
En e$ ser '#mano est&n conser>a"os tam)i?n e$ or"en "e $os genes +o- a $o
$argo "e$ e:e anteroposterior * $a $oca$i/aci2n cromos2mica%
Se $es "enomina +O@ en '#manos * +o- en >erte)ra"os%
En $os >erte)ra"os tienen 1#e >er con $a segmentaci2n craneoca#"a$
Los genes son acti>a"os * e-presa"os en $a "irecci2n 45 E 85% .4 prima, 8
prima0
Los genes 45se e-presan m&s temprano * m&s anteriormente%
S# reg#$aci2n: comp$e:a
En >erte)ra"os 'a*: +o-a, +o-), +o-c, +o-"%
E$ rat2n * e$ ser '#mano contienen a$ menos 4I genes 'omeoca:a #)ica"os en (
cromosomas "i!erentes% En Drosop'i$a son G genes%
Se >e $a act#aci2n "e $os genes +o- en e$ e:e principa$ "e$ c#erpo, intestino, $os
miem)ros, $as c?$#$as sang#neas * $os genita$es internos * e-ternos%
7oma"o "e Langman 2010: As, $os genes 1#e "eterminan estr#ct#ras m&s
cranea$es se enc#entran en e$ e-tremo45"e$ ADN * se e-presan $os primeros,
mientras 1#e $os genes 1#e contro$an e$ "esarro$$o posterior se e-presan
consec#ti>amente * se "isponen "e !orma sec#encia$ 'acia e$ e-tremo 85% Estos
genes se conser>an en e$ ser '#mano en c#arto copias, +O@A, +O@B, +O@C
* +O@D, 1#e se "isponen * se e-presan como $o 'acen $os "e Drosop'i$a% 3or
tanto, ca"a gr#po se enc#entra en #n cromosoma "istinto * $os genes "e ca"a
gr#po se n#meran "e$ 1 a$ 14% Los genes con e$ mismo n6mero 1#e pertenecen a
gr#pos "istintos !orman #n gr#po par&$ogo como +O@A(, +O@B(, +O@C( *
+O@D(% E$ patr2n "e e-presi2n "e estos genes, :#nto con $os "atos aporta"os
por e-perimentos rea$i/a"os en ratones con genes inacti>a"os .JnocJEo#t0 1#e
carecen "e #no o m&s "e estos genes, apo*an $a 'ip2tesis "e 1#e estos genes
participan en el esta-lecimiento del e*e craneocaudal de los deri.ados de las
/ capas germinati.as0
name chromosome gene
+01A *or
sometimes
+01!,
-HOXA@
chromosome 2
+01A!, +01A", +01A), +01A/, +01A3, +01A4, +01A2, +01A5,
+01A!6,+01A!!, +01A!)
+017
- HOXB@
chromosome !2
+017!, +017", +017), +017/, +0173, +0174, +0172,
+0178, +0175,+017!)
+01.
- HOXC@
chromosome !"
+01./, +01.3, +01.4, +01.8, +01.5, +01.!6, +01.!!,
+01.!", +01.!)
+01D
- HOXD@
chromosome "
+01D!, +01D), +01D/, +01D8, +01D5, +01D!6,
+01D!!, +01D!", +01D!)
1- Genes (a2 3(aired -o24
La !ami$ia g?nica 3a-:
I miem)ros%
Las protenas 3a- contienen #n "ominio par "e 12G amino&ci"os, 1#e se #ne a$
ADN
DesempeDan !#nciones importantes en $os 2rganos "e $os senti"os * e$ sistema
ner>ioso
Paired box (Pax) genes are a family of tissue specific transcription
factors containing a paired domain and usually a partial or complete
homeodomain. An octapeptide may also be present. 9ax proteins are important
in early animal development for the specification of specific tissues, as well as
during epimorphic limb regeneration in animals capable of such.
MIEMBROS
9A1! has been identified in mice with the development of vertebrate and
embryo segmentation, and some evidence this is also true in humans. :t
transcribes a //6 amino acid protein from / exons and !,)")bps in humans.

9A1" has been identified with &idney and optic nerve development. :t
transcribes a /!2 amino acid protein from !! exons and /,"4! bps in
humans. (utation of 9A1" in humans has been associated with renal-
coloboma syndrome as well as oligomeganephronia.
!#

9A1) has been identified with ear, eye and facial development. :t
transcribes a /25 amino acid protein in humans. (utations in it can
cause ;aardenburg syndrome. 9A1) is fre<uently expressed
in melanomas
"#
and contributes to tumor cell survival.
)#
9A1/ has been identified with pancreatic islet beta cells. :t transcribes a
)36 amino acid protein from 5 exons and ",6!6 bps in humans.
9A13 has been identified with neural and spermatogenesis development
and b-cell differentiation. :t transcribes a )5! amino acid protein from !6
exons and ),4//bps in humans.
9A14 is the most researched and appears throughout the literature as a
=master control= gene for the development of eyes and sensory organs,
certain neural and epidermal tissues as well as
other homologous structures, usually derived from ectodermal tissues.

9A12 has been possibly associated with myogenesis. :t transcribes a

protein of 3"6 amino acids from 8 exons and ","46bps in humans. 9A12
directs postnatal renewal and propagation of myogenic satellite cells but not
for the specification.
/#
9A18 has been associated with thyroid specific expression. :t transcribes
a protein of /3! amino acids from !! exons and ",3"4bps in humans.
9A15 has found to be associated with a number of organ and other
s&eletal developments, particularly teeth. :t transcribes a protein of )/!
amino acids from / exons and !,4//bps in humans.
%- Familia de los genes (&5
Inc$#*e: 3itE1 gen 6nico e-presa"o en $a pit#itaria
OctE1 * Oct B 4
UncEGA #n gen e-presa"o en #n nemato"o
Estos genes contienen #na 'omeosec#encia, #na regi2n 1#e co"i!ica K8
amino&ci"os * 1#e tam)i?n se #ne a$ ADN a tra>?s "e #na estr#ct#ra '?$iceE$a/oE
'?$ice%
E$ gen OctE( "esempeDa #n pape$ importante en $os esta"ios inicia$es "e $a
segmentaci2n%
&ct-6 pertenece a este grupo de genes
Contiene 'omeoca:a, a"em&s #na regi2n "e K8 amino&ci"os 1#e tam)i?n se #nen
a$ ADN a tra>?s "e #na '?$iceEasaE'?$ice
D- Las prote7nas Lim
Constit#*e #na gran !ami$ia "e protenas con 'omeo"ominio, a$g#nas "e $as
c#a$es se #nen a$ ADN en e$ n6c$eo * otras est&n #)ica"as en e$ citop$asma%
E- La )amilia del gen Dl23Distalless4:
+a* A miem)ros
Operan en pares $os c#a$es est&n estrec'amente asocia"os con $os genes +o-
D$-E8 * D$-EA est&n $oca$i/a"os en posici2n 8L .8 prima0 en re$aci2n a +o-aE14
D$-E4 * D$-EK son 85 a +o-)E14
D$-E1 * D$-E2 son 85a +o-"E14
La !ami$ia "e genes Dl2: contiene A miem)ros * "esempeDan !#nciones
importantes en $os procesos "e esta)$ecimiento "e$ patr2n corpora$ .en especia$
$os es)o/os "e $os miem)ros0% Los genes D$- "e $os mam!eros act6an en pare:as
* m#estran #na asociaci2n estrec'a con $os +o-% 7am)i?n inter>ienen en $a
!ormaci2n "e ma-i$ares * o"o interno
7ra)a:an en e$ "esarro$$o "e $os ap?n"ices * en $a mor!og?nesis "e $a man")#$a
* "e$ o"o interno%
F- Los genes Ms2 3muscle segment $omeo-o24
Dos miem)ros, Ms-E1 * Ms-E2
Son in'i)i"ores "e $a "i!erenciaci2n en etapa prenata$, mientras 1#e en etapa pos
nata$ mantienen $a capaci"a" "e pro$i!eraci2n "e $os te:i"os%
Importantes en $as re$aciones epite$ioEmesen1#imatosas en $as e-tremi"a"es * $a
cara%
8- Los genes #--o2: .7)-0
7ienen #na regi2n conser>a"a, $a ca:a 7, 1#e co"i!ica "e 1G0 a 200 amino&ci"os,
1#e se #ne en !orma espec!ica a$ ADN
+a* m&s "e 100 miem)ros%
7ienen 1#e >er con $a in"#cci2n "e$ meso"ermo, * si $a e-tremi"a" en "esarro$$o
es #n )ra/o o #na pierna
T-box refers to a group of transcription factors involved
in limb and heart development
>enes encoding T-box proteins include$
T7'! *TBR1,
T71! *TBX1,
T71" *TBX2,
T71) *TBX3,
T71/ *TBX4,
T713 *TBX5,
T714 *TBX6,
T71!6 *TBX10,
T71!3 *TBX15,
T71!8 *TBX18,
T71!5 *TBX19,
T71"6 *TBX20,
T71"! *TBX21,
T71"" *TBX22,
/- Los )actores de transcripcin $lice 9 lao 9 $lice
AE 3rotenas )&sicas '?$ice B $a/o B '?$ice
3rotenas 1#e contienen #n corto tramo "e amino&ci"os en $a c#a$ "os '?$ices
a$!a son separa"as por #n $a/o .$oop0 "e amino&ci"os% Esta regi2n, con #na
regi2n )&sica a"*acente, permite a esta protena reg#$a"ora #nirse a sec#encias
espec!icas "e ADN%
Las regiones )&sicas "e estas protenas se #nen a$ ADN,
E$ "ominio '?$iceE$a/oE'?$ice est& in>o$#cra"o en 'omo"imeri/aci2n o
'etero"imeri/aici2n%
Com6n en genes 1#e reg#$an $a miog?nesis%
BE <ami$ia "e $os genes <orJ'ea"
M&s "e 100 miem)ros
Este gr#po "e protenas tienen en com6n #na regi2n "e #ni2n a$ ADN en !orma
"e '?$ice a$a"a .Minge" '?$i- str#ct#re0
The motif is characteri%ed by two ? -helices connected by a loop. :n general,
transcription factors including this domain are dimeric, each with one helix
containing basic amino acidresidues that facilitate DNA binding.
3#
:n general,
one helix is smaller, and, due to the flexibility of the loop, allows dimeri%ation by
folding and pac&ing against another helix. The larger helix typically contains the
DNA-binding regions. b+@+ proteins typically bind to aconsensus
se<uence called an A-box, .ANNT>.
4#
The canonical A-box is .A.>T>
*palindromic,, however some b+@+ transcription factors, notably those of the
b+@+-9ABfamily, bind to related non-palindromic se<uences, which are similar
to the A-box.
Axamples of transcription factors containing a b+@+ include$
Ah'
7eta"CNeuroD!
7(A@-!-.@0.D
.-(yc, N-(yc
(yoD
(yf3
9ho/
+:E
:.A!
N9AB!, N9AB), (093
Bcl, also &nown as Tal!
proneural b+@+ genes li&e p-.a(D::, and pBer*))4,NeuroD.
Bcleraxis
Neurogenins
(A1
0@:>!, 0@:>"
6- Factores de transcripcin en dedos de inc
3rotenas 1#e tienen #)ica"os en !orma reg#$ar #ni"a"es "e cisti"ina e 'isti"ina,
1#e est&n #ni"os a iones "e /inc 1#e ca#sa 1#e $a ca"ena "e po$ip?pti"os se
"o)$e en estr#ct#ras como "e"os%
Estos "e"os se #nen a $#gares espec!icos a$ ADN
Inc$#*e a $as sig#ientes !ami$ias:
AE Los genes So-
Genes 'o2: prote7nas 'o2
Constit#*en #na gran !ami$ia .m&s "e 20 miem)ros0, s#s componentes tienen en
com6n #n "ominio +MF .gr#pos "e mo>i$i"a" a$ta0 en $a protena% Este
"ominio, :#nto a #na protena compaDera .asocia"a0, se #ne a siete n#c$e2ti"os
en e$ s#rco menor * no en e$ s#rco ma*or "e $a '?$ice "e ADN * pro>oca #n
cam)io importante en s# con!ormaci2n%
Una caracterstica "e $os genes So- es 1#e tra)a:an en con:#nto con otros
!actores "e transcripci2n, para $ograr $a e-presi2n "e $os genes%
El gen '!; es de este grupo0
Se e-presan en to"as $as estr#ct#ras en "i!erentes etapas "e$ "esarro$$o%
Otros !actores "e transcripci2n:
Box genes are classified into groups. Box genes from different groups share little similarity
outside the DNA-binding domain. :n mouse and human the members of the groups are$
/#
BoxA$ SRY
Box7!$ SOX1, SOX2, SOX3
Box7"$ SOX14, SOX21
Box.$ SOX4, SOX11, SOX12
BoxD$ SOX5, SOX6, SOX13
BoxA$ SOX8, SOX9, SOX10
BoxE$ SOX7, SOX17, SOX18
Box>$ SOX15
Box+$ SOX30
II- M&LE%5LA' DE 'E<ALI=A%I>N:
Estas sa$en "e $as c?$#$as 1#e $as pro"#cen * e:ercen s#s e!ectos so)re otras c?$#$as, 1#e
p#e"en estar cerca o a gran "istancia% Se 'a "esc#)ierto 1#e $a misma mo$?c#$a "e
seDa$i/aci2n p#e"e ser #sa"a en "i!erentes $#gares * en "i!erentes etapas "e$ "esarro$$o
"e$ em)ri2n%
Los !actores 1#e contro$an $oca$mente, ta$es como $a "#raci2n o $a concentraci2n "e $a
mo$?c#$a "e seDa$i/aci2n, "eterminan e$ "estino "e$ gr#po "e c?$#$as respon"e"oras%
Estas mo$?c#$as seDa$i/a"oras se #nen a mo$?c#$as receptoras, 1#e s#e$en ser protenas
transmem)rana 1#e protr#*en a tra>?s "e $a mem)rana p$asm&tica "e $as c?$#$as% Con $a
#ni2n oc#rre #na casca"a "e !en2menos en #na >a "e trans"#cci2n "e seDa$, 1#e 'ace
1#e $a seDa$ $$eg#e 'asta e$ n6c$eo%
A signaling molecule is a molecule involved in transmitting information
between cells of a living multicellular organism, or between organisms of the
same or different species.
:n a multicellular organism, signaling between cells occurs either through
release into the extracellular space, divided in paracrine signaling *over short
distances, and endocrine signaling *over long distances,, or by direct contact,
&nown as juxtacrine signaling.
!#
Autocrine signaling is a special case of
paracrine signaling where the secreting cell has the ability to respond to the
secreted signaling molecule.
"#
Bynaptic signaling is a special case of paracrine
signaling *for chemical synapses, or juxtacrine signaling *for electrical
synapses, between neurons and target cells. Bignaling molecules interact with
a target cell as a ligand to cell surface receptors, andCor by entering into the cell
through its membrane or endocytosis for intracrine signaling. This generally
results in the activation of second messengers, leading to various physiological
effects.
+ormones are the major signaling molecules of the endocrine system,
though they often regulate each otherFs secretion via local signaling
*e.g. islet of @angerhans cells,, and most are also expressed in tissues for
local purposes *e.g. angiotensin, or failing that,structurally related molecules
are *e.g. 9T+r9,.
Neurotransmitters are signaling molecules of the nervous system, also
including neuropeptides and neuromodulators. Neurotransmitters li&e
the catecholamines are also secreted by the endocrine system into the
systemic circulation.
.yto&ines are signaling molecules of the immune system, with a primary
paracrine or juxtacrine role, though they can during significant immune
responses have a strong presence in the circulation, with systemic effect
*altering iron metabolism or body temperature,. >rowth factors can be
considered as cyto&ines or a different class.
?- <ami$ia "e$ )actor de crecimiento trans)ormante: #GF-@%
Son #nas 40 mo$?c#$as%
Como e:emp$o est& 7F<E N1: es #n "mero #ni"o por #n p#ente "is#$!#ro,
sinteti/a"o en !orma "e #n par "e prec#rsores inacti>os "e 4I0 amino&ci"os% E$
prec#rsor g$icosi$a"o est& constit#i"o por #na pe1#eDa sec#encia NEtermina$
seDa$i/a"ora, #na proregi2n m#c'o ma*or * #na regi2n C termina$ "e 112
amino&ci"os )ioacti>a% La proregi2n es escin"i"a 12arngea12amente "e $a regi2n
)ioacti>a por #na /ona "e c#atro amino&ci"os )&sicos #)ica"a :#nto a$ "ominio
)ioacti>o% 7ras s# secreci2n por $a c?$#$a, $a proregi2n "e $a mo$?c#$a permanece
asocia"a a $a regi2n )ioacti>a, 'acien"o 1#e $a mo$?c#$a se mantenga en esta"o
$atente% El d7mero -ioacti.o slo adquiere su acti.idad -iolgica tras la
disociacin entre la proregin A la regin -ioacti.a0
Una "e $as s#)!ami$ias m&s importantes "e $a !ami$ia "e #GF-@ , es $a !ami$ia "e $as
protenas mor!ogen?ticas 2seas% L$e>an este nom)re por1#e inicia$mente se
"esc#)rieron como $os agentes in"#ctores "e$ proceso "e c#raci2n "e #na !ract#ra%
Son 18 miem)ros% O#egan #n pape$ importante en e$ "esarro$$o "e $a ma*or parte "e
$as estr#ct#ras "e$ em)ri2n%
Us#a$mente e:ercen s# e!ecto in'i)ien"o otros procesos en e$ em)ri2n%
3ara 'acer m&s comp$ica"o esto a$g#nos procesos "e$ "esarro$$o oc#rren por $a
in'i)ici2n "e BM3s, como en e$ caso "e$ "esarro$$o "e$ sistema ner>ioso centra$%
Las mo$?c#$as 1#e in'i)en o antagoni/an $a acci2n "e $as BM3s son: estas
mo$?c#$as se #nen a $os "meros "e BM3s secreta"os, e inter!ieren con s# #ni2n a
receptores espec!icos%
Miem)ro <#nciones 1#e representa
De 7F<E N1 a 7F<E N8 In"#cci2n meso"?rmica
3ro$i!eraci2n "e mio)$astos
In!i$traci2n "e $a ge$atina car"iaca por c?$#$as en"ote$ia$es
a#ric#$o>entric#$ares
Acti>ina 3ro$i!eraci2n "e c?$#$as "e $a gran#$osa
In"#cci2n meso"?rmica
In'i)ina In'i)ici2n "e $a secreci2n "e gona"otropinas por $a
'ip2!isis
S#stancia "e in'i)ici2n
m#$$eriana
Regresi2n "e $os con"#ctos parameson?!ricos
Decapentap$?:ico SeDa$i/aci2n para e$ "esarro$$o "e $os miem)ros
Pg1 In"#cci2n "e$ meso"ermo * $a $nea primiti>a
De BM3E1 a BM3EI In"#cci2n "e $a p$aca ne#ra$, "i!erenciaci2n es1#e$?tica *
otras in"#cciones
No"a$ <ormaci2n "e$ meso"ermo * "e $a $nea primiti>a, !i:aci2n
a-ia$ i/1#ier"a B "erec'a
<actor ne#rotr2pico
"eri>a"o "e $a $nea "e
c?$#$as g$ia$es
In"#cci2n "e$ crecimiento "e$ es)o/o #retera$,
co$oni/aci2n ne#ra$ "e$ intestino
Le!t* Determinaci2n "e $a asimetra corpora$
T>E-G is a secreted protein that exists in at least three isoforms called T>E-
G !, T>E- G " and T>E- G ). :t was also the original name for T>E-G!, which was
the founding member of this family. The T>E-G family is part of a superfamily of
proteins &nown as the transforming growth factor beta superfamily, which
includes inhibins, activin, anti-mHllerian hormone, bone morphogenetic
protein, decapentaplegic and Ig-!.
T>E-G pertenece a una superfamilia de factores de crecimiento <ue incluye
tres isoformas para T>E-G *!,",), y otros factores variados,
como 7(9, activinas, inhibinas y la hormona antimHlleriana.
!
@a molJcula con
una funciKn mLs amplia es T>E-G! y es la <ue se utili%a como factor de
referencia. As una proteMna homodimJrica, producida por una gran variedad de
cJlulas, como pla<uetas, cJlulas endoteliales, linfocitos y macrofagos. Be
sinteti%a como un precursor inactivo, <ue debe ser escindido proteolMticamente
para generar la proteMna activa. Asta se une a dos receptores celulares *tipo : y
::, con actividad serina-treonina &inasa, y desencadena la fosforilaciKn de
factores citoplLsmicos denominados Bmads, de los <ue existen diferentes
formas *!,",),3,8,. Astos Bmads fosforilados se unen a Bmad/ para formar
heterodMmeros <ue entran en el nNcleo y se asocian a otras proteMnas de uniKn
a ADN para activar o inhibir la transcripciKn de genes especMficos. T>E-G tiene
muchos efectos diferentes *se dice por ello <ue tiene un efecto pleiotrKpico,, a
veces opuestos, en funciKn del tipo de tejido afectado y el tipo de daOo.
8- La !ami$ia FA%#&! DE %!E%IMIEN#& FI1!&1LB'#I%&
<ami$ia con 22 miem)ros
Los !actores "e crecimiento !i)ro)$&stico secreta"os se asocian "e !orma estrec'a a
$a matri/ e-trace$#$ar * tiene 1#e #nirse a$ s#$!ato "e 'epar&n para acti>ar s#s
receptores%
Estim#$an entre otros e$ crecimiento "e $os capi$ares
S# reg#$aci2n:
aE mo"i!icaci2n "e s# interacci2n con 'eparan proteog$icanos en e$ comp$e:o con e$
receptor
)E reg#$aci2n a ni>e$ "e $a mem)rana "e $a c?$#$a respon"e"ora a tra>?s "e $a acci2n
"e protenas transmem)rana
cE reg#$aci2n interce$#$ar por mo$?c#$as ta$es como spro#t*, $a c#a$ 'ace comp$e:os
con partes "e $a ma1#inaria "e $a >a "e trans"#cci2n "e $a c?$#$a respon"e"ora%
<F< Sistema en "esarro$$o
<F<E1 Estim#$aci2n "e $a pro$i!eraci2n "e 1#eratinocitos
In"#cci2n 'ep&tica inicia$
<F<E2 Estim#$aci2n "e $a pro$i!eraci2n "e 1#eratinocitos
In"#cci2n "e$ crecimiento pi$oso
Cresta ecto"?rmica apica$ en e$ crecimiento "e $os miem)ros
Estim#$a $a pro$i!eraci2n "e$ mesen1#ima "e $os ma-i$ares
In"#cci2n 'ep&tica temprana
In"#cci2n "e $os t6)#$os rena$es
<F<E4 <ormaci2n "e$ o"o interno
<F<E( Mantenimiento "e $a acti>i"a" mit2tica en e$ tro!o)$asto
Creta ecto"?rmica apica$ en e$ crecimiento "e $os miem)ros
Es)o/o "e$ esma$te en $os "ientes en "esarro$$o
Estim#$a $a pro$i!eraci2n "e$ mesen1#ima "e $os ma-i$ares
<F<E8 Estim#$a $a !ormaci2n "e $a p$aco"a ecto"?rmica
<F<EG Organi/a"or istmito, patr2n "e$ 1(arngea1(am
Cresta ecto"?rmica apica$ en e$ crecimiento "e $os miem)ros
Des"e $a cresta ne#ra$ anterior reg#$a e$ "esarro$$o "e $as >esc#$as
2pticas * "e$ te$enc?!a$o
In"#cci2n temprana "e $os "ientes
Estim#$a $a pro$i!eraci2n "e$ meso"ermo "e $a cresta ne#ra$ en $a
regi2n !rontonasa$
Estim#$a $a pro$i!eraci2n "e$ mesen1#ima "e $os ma-i$ares
In"#cci2n "e $as papi$as !i$i!ormes "e $a $eng#a
In"#cci2n 'ep&tica temprana
Crecimiento "e$ t#)?rc#$o genita$
<F<E10 In"#cci2n "e $os miem)ros
Mor!og?nesis "e rami!icaci2n en e$ p#$m2n en "esarro$$o
In"#cci2n "e $a pr2stata
Crecimiento "e$ t#)?rc#$o genita$
:n humans, "" members of the E>E family have been identified, all of which
are structurallrelated signaling molecules$
!#"#)#
(embers E>E! through E>E!6 all bind fibroblast growth factor
receptors *E>E's,. E>E!is also &nown as ac!"!c, and E>E" is also &nown as #as!c
$!#r%#last &r%'t( $act%r.

(embers E>E!!, E>E!", E>E!), and E>E!/, also &nown as E>E homologous factors
!-/ *E+E!-E+E/,, have been shown to have distinct $u)ct!%)al differences compared to the
E>Es. Although these factors possess remar&ably similar se<uence homology, they do not
bind E>E's and are involved in intracellular processes unrelated to the E>Es.
/#
This group
is also &nown as =iE>E=.
3#

+uman E>E!8 is involved in cell development and morphogenesis in various tissues

including cartilage.
4#

+uman E>E"6 was identified based on its homology to X*)%+us E>E-"6 *1E>E-"6,.
2#8#

E>E!3 through E>E") were described later and functions are still being
characteri%ed. E>E!3 is the mouse ortholog of human E>E!5*there is no human E>E!3,
and, where their functions are shared, they are often described as E>E!3C!5.
5#
:n contrast
to the local activity of the other E>Es, E>E!3C!5, E>E"! and E>E") have systemic effects.
5#!6#
Receptors[edit source | edit beta]
The mammalian fibroblast growth factor receptor family has /
members, E>E'!, E>E'", E>E'), and E>E'/. The E>E's consist of three
extracellular immunoglobulin-type domains *D!-D),, a single-span trans-
membrane domain and an intracellular split tyrosine &inasedomain. E>Es
interact with the D" and D) domains, with the D) interactions primarily
responsible for ligand-binding specificity *see below,. +eparan sulfate binding is
mediated through the D) domain. A short stretch of acidic amino acids located
between the D! and D" domains has auto-inhibitory functions. This Facid boxF
motif interacts with the heparan sulfate binding site to prevent receptor
activation in the absence of E>Es.
<UNCIONES
Thus the functions of E>Es in developmental processes
include mesoderm induction, antero-posterior patterning,
2#
limb development,
neural induction and neural development,
!4#
and in mature
tissuesCsystemsangiogenesis, &eratinocyte organi%ation, and wound
healing processes.
0ne important function of E>E! and E>E" is the promotion of endothelial
cell proliferation and the physical organi%ation of endothelial cells into tube-li&e
structures. They thus promote angiogenesis, the growth of new blood
vessels from the pre-existing vasculature. E>E! and E>E" are more potent
angiogenic factors than vascular endothelial growth factor *IA>E, orplatelet-
derived growth factor *9D>E,.
""#
E>E! has been shown in clinical experimental
studies to induce angiogenesis in the heart.
"!#
/- Familia $edge$og
4 miem)ros: sonic, in"ian, "esert
Uno "e s#s miem)ros Sonic 'e"ge'og, res#$ta !#n"amenta$
3rotena con #na porci2n nEtermina$ a$tamente conser>a"a * #na regi2n cE
termina$ m&s >aria)$e%
L#ego "e $a sntesis * $i)eraci2n "e$ po$ip?pti"o por e$ retc#$o en"op$asmico, e$
p?pti"o "e seDa$ es separa"o * oc#rre g$icosi$aci2n en e$ resto "e$ p?pti"o% A#n
"entro "e $a c?$#$a, e$ p?pti"o s'' s#!re a#torompimiento a tra>?s "e $a acti>i"a"
cata$tica "e s# porci2n cEtermina$% D#rante s# rompimiento, $a porci2n nE
termina$ se #ne a$ co$estero$% Esta mo$?c#$a "e 1I Da$tons, nEtermina$, #ni"a a$
co$estero$ es secreta"a "e $a c?$#$a% 7o"a $a acti>i"a" "e seDa$i/aci2n "e s''
resi"e en esta porci2n nEtermina$%
En $a s#per!icie "e $a c?$#$a )$anco, se #ne a #n receptor $$ama"o patc$ed, este
est& estrec'amente re$aciona"o con #na mo$?c#$a transmem)rana, #na protena
$$ama"a smoot$ened% Norma$mente patc$ed in'i)e $a acti>i"a" "e seDa$i/aci2n
"e smoot$ened% S'' a$ #nirse a patc'e" permite a smoot'ene" 1#e en>e #na
seDa$ a$ interior "e $a c?$#$a%
'$$ in'i)e $a acti>i"a" in'i)itoria "e patc$ed0
A tra>?s "e $a participaci2n "e otras mo$?c#$as en e$ citop$asma, $as c#a$es est&n
norma$mente #ni"as a microt6)#$os, !ina$mente smoot$ened acti>a e$ !actor "e
transcripci2n ;"e"o /inc 8= .8E/inc !inger0 $$ama"o Gli, e$ c#a$ se m#e>e a$
interior "e$ n6c$eo * se #ne a #n sitio espec!ico "e$ ADN%
The hedgehog gene *((, was first identified in the fruit-fly Dr%s%+(!la
,*la)%&ast*r.
0f the (( homologues, SHH has been found to have the most critical roles in
development, acting as a morphogen involved in patterning many systems,
including the limb
3#
and midline structures in the brain,
!"#
spinal cord,
!)#
the thalamus by the-%)a l!,!ta)s !)trat(ala,!ca
!/#
and the teeth.
!3#
(utations
in the human sonic hedgehog gene, SHH, cause holoprosencephaly type )
+9A) as a result of the loss of the ventral midline
Patterning of the central nervous system[edit source | edit beta]
The sonic hedgehog *B++, signaling molecule assumes various roles in
patterning the central nervous system *.NB, during vertebrate development.
0ne of the most characteri%ed functions of B++ is its role in the induction of
the floor plate and diverse ventral cell types within the neural tube.
"6#
The notochord, a structure derived from the axial mesoderm, produces B++
which travels extracellularly to the ventral region of the neural tube and instructs
those cells to form the floor plate.
"!#
Another view for floor plate induction
hypothesi%e that some precursor cells located in notochord are inserted into the
neural plate before its formation, later giving rise to floor plate.
""#
B++ exerts its effects in a concentration-dependent manner,
"8#
so that a high
concentration of B++ results in a local inhibition of cellular proliferation.
"5#
This
inhibition causes the floor plate to become thin compared to the lateral regions
of the neural tube. @ower concentration of B++ results in cellular proliferation
and induction of various ventral neural cell types.
"4#
0nce the floor plate is
established, cells residing in this region will subse<uently express B++
themselves
"5#
generating a concentration gradient within the neural tube
Morphogenetic activity[edit source | edit beta]
The concentration and time dependent cell fate determining activity of B++ in
the ventral neural tube ma&es it a prime example of amorphogen. :n
vertebrates, B++ signaling in the ventral portion of the neural tube is most
notably responsible for the induction of floor platecells and motor neurons.
/4#
B++ emanates from the notochord and ventral floor plate of the developing
neural tube to create aconcentration gradient that spans the dorso-ventral axis.
/2#
+igher concentrations of the B++ ligand are found in the most ventral
aspects of the neural tube and notochord, while lower concentrations are found
in the more dorsal regions of the neural tube.
/2#
The B++ concentration
gradient has been visuali%ed in the neural tube of mice engineered to express a
B++$$>E9 fusion protein to show this graded distribution of B++ during the
time of ventral neural tube patterning.
/8#
6- Familia Cnt
1G miem)ros
O#ega #n pape$ ma*or en e$ proceso "e $a gastr#$aci2n .tercera semana "e$
"esarro$$o0
La !orma en 1#e act6a es comp$e:a% Lo 'ace a tra>?s "e )etaEcatenina% En
a#sencia "e Cnt, en e$ interior "e $a c?$#$a, )eta catenina est& #ni"a a #n
comp$e:o "e "estr#cci2n * es "egra"a"a% C#an"o se presenta Cnt, se #ne a #n
receptor en $a s#per!icie "e $a c?$#$a $$ama"o <ri//$e" * acti>a #na seg#n"a
mo$?c#$a $$ama"a Dis'e>e$e", $a c#a$ pre>iene $a "egra"aci2n "e )eta ca"enina%
Beta ca"enina entonces entra a$ n6c$eo en "on"e !orma comp$e:os con otros
!actores "e transcripci2n, para !ina$mente #nirse a$ ADN * acti>ar $a
transcripci2n%
Reg#$aci2n: s# acti>i"a" p#e"e ser in'i)i"a por otras mo$?c#$as in'i)itorias% E$
<actor in')itorio "e Cnt E1 * cer)er#s, se #nen "irectamente a Cnt * DicJJop!
e:erce s# e!ecto a$ #nirse a$ comp$e:o receptor%
Three ;nt signaling pathways have been characteri%ed$ the canonical ;nt
pathway, the noncanonical planar cell polarity pathway, and the noncanonical
;ntCcalcium pathway. All three ;nt signaling pathways are activated by the
binding of a ;nt-protein ligand to a Eri%%led family receptor, which passes the
biological signal to the protein Dishevelledinside the cell. The canonical ;nt
pathway leads to regulation of gene transcription, the noncanonical planar cell
polarity pathway regulates the cytos&eleton that is responsible for the shape of
the cell, and the noncanonical ;ntCcalcium pathway regulates calciuminside the
cell. ;nt signaling pathways use either nearby cell-cell communication
*paracrine, or same-cell communication *autocrine,. They are highly
evolutionarily conserved, meaning they are similar across many species from
fruit flies to humans.
!#"#
The discovery of ;nt signaling was influenced by research
on oncogenic retroviruses. :n !58", 'oel Nusse and +arold Iamus infected
mice with mouse mammary tumor virus to see which mouse genes would
produce
clar!$!cat!%) )**"*"#
breast tumors upon mutation. They identified a new mouse
proto-oncogene that they named int! *integration !,.
3#"#
The importance of int! was not fully appreciated until researchers noted that it
had a high degree of conservation across several species, including humans
and Dr%s%+(!la. :ts presence in Dr%s%+(!la ,*la)%&ast*r was particularly
important because in !582, researchers were able to determine that the int!
gene in Dr%s%+(!la was actually the already characteri%ed Dr%s%+(!la gene
&nown as ;ingless *;g,. This meant that the mammalian int! was
the homologue of ;g.
"#
Proteins[edit source | edit beta]
.rystal protein structure of ;nt8 and the cysteine-rich domain of Eri%%led 8.
The ;nt proteins are a diverse family of secreted lipid-modified
signaling glycoproteins that are )36-/66 amino acids in length.
2#
The type of
lipid modification that occurs on these proteins ispalmitoylation of cysteines in a
conserved pattern of ")-"/ cysteine residues.
)#
9almitoylation is necessary
because it initiates targeting of the ;nt protein to the plasma membrane for
secretion and it allows the ;nt protein to bind its receptor. ;nt proteins also
undergoglycosylation, which insures proper secretion.
8#
:n ;nt signaling, these
proteins act as ligandsto activate the different ;nt pathways via paracrine and
autocrine routes.
!#/#
pecies !nt proteins
H%,% sa+!*)s
;nt!, ;nt", ;nt"7, ;nt), ;nt)A, ;nt/, ;nt3A,
;nt37, ;nt4, ;nt2A,;nt27, ;nt8A, ;nt87, ;nt5A,
;nt57, ;nt!6A, ;nt!67, ;nt!!, ;nt!4
"oundation[edit source | edit beta]
;nt signaling begins when one of the ;nt proteins binds the N-terminal extra-
cellular cysteine-rich domain of a Eri%%led *E%, family receptor.
!6#
These
receptors span the plasma membrane seven times and constitute a distinct
family of >-protein coupled receptors *>9.'s,.
!!#
+owever, to facilitate ;nt
signaling, co-receptors may also be re<uired alongside the interaction between
the ;nt protein and E% receptor. Axamples include lipoprotein receptor-related
protein *@'9,-3C4, receptor tyrosine &inase *'y&,, and '0'".
/#
Ppon activation
of the receptor, a signal is sent to the phosphoprotein Dishevelled *Dsh,, which
is located in thecytoplasm. This signal is transmitted via a direct interaction
between E% and Dsh. Dsh proteins are present in all organisms and they all
share the following highly conserved protein domains$ an amino-
terminal D:1 domain, a central 9DQ domain, and a carboxy-
terminal DA9 domain. These different domains are important because after
Dsh, the ;nt signal can branch off into several different pathways and each
pathway interacts with a different combination of the three domains.
!"#
Eigure !. ;nt doesnFt bind to the receptor. Axin, >BD and A9. form a =destruction complex,= and G-.at
is destroyed.
Eigure ". ;nt binds to *activates, the receptor. Axin is removed from the =destruction complex.= G-.at
moves into the nucleus, binds to a transcription factor on DNA, and activates transcription of a protein.
=9= represents phosphate.
#anonical and noncanonical path$ays[edit source | edit beta]
The three best characteri%ed ;nt signaling pathways are the canonical ;nt
pathway, the noncanonical planar cell polarity pathway, and the noncanonical
;ntCcalcium pathway. As their names suggest, these pathways belong to one of
two categories$ canonical or noncanonical. The difference between the
categories is that a canonical pathway involves the protein G -cateninwhile a
noncanonical pathway operates independently of it.
!6
The canonical !nt path$ay[edit source | edit beta]
The canonical !nt path$ay *or ;ntCG-catenin pathway, is the ;nt pathway
that causes an accumulation of G-catenin in the cytoplasm and its eventual
translocation into the nucleus to act as a
transcriptional coactivator of transcription factors that belong to the T.EC@AE
family. ;ithout ;nt signaling, the G-catenin would not accumulate in the
cytoplasm since a destruction complex would normally degrade it. This
destruction complex includes the following proteins$ Axin, adenomatosis
polyposis coli *A9.,, protein phosphatase "A *99"A,, glycogen synthase
&inase ) *>BD), and casein &inase ! ? *.D!?,. :t degrades G-catenin by
targeting it for ubi<uitination, which subse<uently sends it to the proteasome to
be digested.
!6#!)#
+owever, as soon as ;nt binds E% and @'9-3C4, the
destruction complex function becomes disrupted. This is due to ;nt causing the
translocation of both a negative regulator of Axin and the destruction complex to
the plasma membrane.
/#
This negative regulator becomes locali%ed to the
cytoplasmic tail of @'9-3C4. 9hosphorylation by other proteins in the destruction
complex subse<uently binds Axin to this tail as well. Axin becomes de-
phosphorylated and its stability and levels are decreased. Dsh then becomes
activated via phosphorylation and its D:1 and 9DQ domains inhibit the >BD)
activity of the destruction complex. This allows G-catenin to accumulate and
locali%e to the nucleus and subse<uently induce a cellular response via gene
transduction alongside the T.EC@AE transcription factors.
/#!)#
The noncanonical planar cell polarity path$ay[edit source | edit beta]
The noncanonical planar cell polarity (P#P) path$ay is one of the two ;nt
pathways that does not involve G-catenin. :t does not use @'9-3C4 as its co-
receptor and is thought to use N'+!, 'y&, 9TD2, or '0'". As in the canonical
;nt pathway, the 9.9 pathway is activated via the binding of ;nt to E% and its
co-receptor. The receptor then recruits Dsh, which uses its 9DQ and DA9
domains to form a complex with Dishevelled-associated activator of
morphogenesis ! *DAA(!,. Daam! then activates the small >-
protein 'ho through a guanine exchange factor. 'ho activates 'ho-associated
&inase *'0.D,, which is one of the major regulators of the cytos&eleton. Dsh
also forms a complex with rac! and mediates profilin binding to actin. 'ac!
activates RND and can also lead to actin polymeri%ation. 9rofilin binding to actin
can result in restructuring of the cytos&eleton and gastrulation.
/#!/#
The noncanonical !nt%calcium path$ay[edit source | edit beta]
The noncanonical !nt%calcium path$ay is the other ;nt pathway that does
not stimulate accumulation of G-catenin. :ts role is to help regulate calcium
release from the endoplasmic reticulum *A', in order to control intracellular
calcium levels. @i&e other ;nt pathways, upon ligand binding, the activated E%
receptor directly interacts with Dsh and activates specific Dsh-protein domains.
The domains involved in ;ntCcalcium signaling are the 9DQ and DA9 domains.
/#
+owever, unli&e other ;nt pathways, the E% receptor also directly interfaces
with a trimeric >-protein. This co-stimulation of Dsh and the >-protein can lead
to the activation of either 9@. or c>(9-specific 9DA. :f 9@. is activated, the
plasma membrane component 9:9" is cleaved into DA> and :9). ;hen :9)
binds its receptor on the A', calcium is released. :ncreased concentrations of
calcium and DA> can activate .dc/" through 9D.. .dc/" is an important
regulator of cell adhesion, migration, and tissue separation. :ncreased calcium
also activates calcineurinand .a(D::. .alcineurin induces activation of the
transcription factor NEAT, which regulates ventral patterning.
/#
.amD:: activates
TAD! and N@D &inase, which can interfere with T.ECS-.atenin signaling in the
canonical ;nt pathway.
!3#
+owever, if 9DA is activated, calcium release from
the A' is inhibited. 9DA mediates this through the inhibition of 9D>, which
subse<uently causes the inhibition of calcium release.
/
&egulation[edit source | edit beta]
:n order to ensure proper functioning, ;nt signaling is constantly regulated at
several points along its signaling pathways. Eor instance, as previously
mentioned, ;nt proteins are palmitoylated. The protein +%rcu+!)* mediates this
palmitoylation process, which means that it helps regulate when the ;nt ligand
is secreted by determining when it is fully formed. Becretion of ;nt protein is
further controlled with proteins such as ')tl*ss and *.*))*ss !)t*rru+t*" and
complexes such as the retromer complex.
/#!)#
Ppon secretion, the ligand can
also be prevented from reaching its receptor through the binding of certain
proteins such as the stabili%ers Dally and glypican ), which inhibit diffusion. At
the E% receptor, the binding of proteins other than ;nt can antagoni%e
signaling. Bpecific antagonists include Dic&&opf*D&&,, ;nt inhibitory factor
! *;:E-!,, secreted Eri%%led-related proteins *BE'9,, .erberus, Er%b, ;ise,
and B0BT. All of these constitute inhibitors of ;nt signalingT however, other
molecules have been shown to act as activators as well. Eor
example, Norrin and '-Bpondin"have been shown to activate ;nt signaling in
the absence of ;nt ligand. :nteractions between different ;nt signaling
pathways also regulate ;nt signling. As previously mentioned, the ;ntCcalcium
pathway can inhibit T.ECG-catenin in order to prevent canonical ;nt pathway
signaling.
/#!)#
'mbryonic development[edit source | edit beta]
;nt signaling plays a critical role in the embryonic development of a variety of
organisms. :t is detected in both vertebrates and invertebrates, including
humans, frogs, %ebrafish, C/ *l*&a)s, Dr%s%+(!la, and numerous others. :t was
first &nown to be involved in the segment polarity of Drosophila, where it helps
to establish anterior and posterior polaritiesT however, it has since then been
implicated in numerous other developmental processes. As its function
in Dr%s%+(!la suggests, it plays a &ey role in body axis formation, particularly
the formation of the anteroposterior and dorsoventral axes. :t is also involved in
the induction of cell differentiation to prompt formation of important organs such
as the lungs and ovaries. ;nt further insures the development of these specific
tissues through proper regulation ofcell proliferation and migration. These are
just a few ;nt functions, but they demonstrate that the numerous functions of
;nt signaling can be divided into one of the following categories$ axis
patterning, cell fate specification, cell proliferation, and cell migration.
!8#
(xis patterning[edit source | edit beta]
:n early embryonic development, the formation of the primary body axes is a
crucial step in establishing the overall body plan of each particular organism.
The different axes include the anteroposterior axis, dorsoventral axis, and right-
left axis. ;nt signaling can be implicated in the formation of the anteroposterior
and dorsoventral axes. ;nt signaling activity in anterior-posterior development
can be seen in several organisms including mammals, fish, and frogs. :n
mammals, the primitive strea& and other surrounding tissues produce the
morphogenic compounds ;nts, 7(9s, E>Es, Nodal, and retinoic acid to
establish the posterior region during late gastrula. These proteins form
concentration gradients and the areas of their highest concentration establish
the posterior region and the areas of their lowest concentration indicate the
anterior region. :n fish and frogs, G-catenin produced by canonical ;nt signaling
causes the formation of organi%ing centers, which, alongside 7(9s, elicits
posterior formation. ;nt involvement in dorsoventral axis formation can be seen
in the activity of the formation of the Bpemann organi%er, which establishes the
dorsal region. .anonical ;nt signaling production G-catenin induces the
formation of this organi%er via the activation of the genes t'!) and s!a,%!s.
!8#!5#
;nt signaling is also involved in the axis formation of specific body parts and
organ systems that are a part of later development. :n vertebrates, sonic
hedgehog *Bhh, and ;nt morphogenetic signaling gradients establish the
dorsoventral axis of the central nervous system during neural tube axial
patterning. +igh ;nt signaling establishes the dorsal region while high Bhh
signaling indicates in the ventral region.
"6#
;nt is also involved in the dorsal-
ventral formation of the central nervous system through its involvement in axon
guidance. ;nt proteins guide the axons of the spinal cord in an anterior-
posterior direction.
"!#
;nt is also involved in the formation of the limb dorsal-
ventral axis. Bpecifically, ;nt2a helps produce the dorsal patterning of the
developing limb.
!8#!5#
#ell fate specification[edit source | edit beta]
.ell fate specification, or cell differentiation, is a cellular process where
undifferentiated cells can become a more speciali%ed cell type. ;nt signaling
induces differentiation of pluripotent stem
cells into mesoderm and endoderm progenitor cells.
""#
These progenitor cells
are then further induced to differentiate into more specific cell types such as
endothelial, cardiac, and vascular smooth muscle lineages.
")#
;nt signaling can
also induce blood formation from stem cells. Bpecifically, ;nt) leads to
mesoderm committed cells with hematopoieticpotential.
"/#
;nt! has also been
shown to antagoni%e neural differentiation and is a major factor in self-renewal
of neural stem cells. This allows for regeneration of nervous system cells, which
is further evidence of a role in promoting neural stem cell proliferation.
""#
;nt
signaling has also been shown to be involved in germ
cell determination, gut tissue specification, hair follicle development, lung tissue
development, trun& neural crest cell differentiation, nephron development, ovary
development, and sex determination.
!8#
#ell proliferation[edit source | edit beta]
:n order to have the mass differentiation of cells needed to form the specified
cell tissues of different organisms, a proliferation, or cell growth, of embryonic
stem cells must ta&e place. This process is mediated through canonical ;nt
signaling, which increases nuclear and cytoplasmic level of G-catenin. :ncreased
levels of G-catenin can initiate transcriptional activation of proteins such
as cyclin D! and c0,c, which control the >! to B phase transition in the cell
cycle. Antry into the B phase causes DNA replication and ultimately mitosis,
which are responsible for cell proliferation.
"3#
This increase in proliferation is
directly paired with cell differentiation because as the stem cells proliferate, they
are differentiated into the specific tissues that are induced to become. This
allows for overall growth and development of specific tissue systems during
embryonic development. This is apparent in systems such as the circulatory
system where ;nt)a leads to proliferation and expansion of hematopoietic
stem cells needed for red blood cell formation.
"4#
#ell migration
.ell migration during embryonic development allows for the establishment of
body axes, tissue formation, limb induction, and several other processes. ;nt
signaling helps mediate this process, particularly during convergent extension.
'esearch has shown that signaling from both the ;nt 9.9 pathway and
canonical ;nt pathway is re<uired for proper convergent extension during
gastrulation. .onvergent extension is further regulated by the ;ntCcalcium
pathway, which bloc&s convergent extension when activated. ;nt signaling also
induces cell migration in later stages of development through the control of the
migration behavior of neuroblasts, neural crest cells, myocytes, and tracheal
cells.
"2#
;nt signaling is also involved in another &ey migration process &nown as the
epithelial-mesenchymal transition *A(T,. This process is what allows epithelial
cells to transform into mesenchymal cells so that they are no longer held in
place at the laminin. :t involves a down-regulation of cadherins so that cells can
detach from laminin and migrate. ;nt signaling is an inducer of A(T,
particularly in mammary development.
"8#
D- %$ordin: noggin A gremlin
E:ercen s# acci2n a$ in'i)ir otras mo$?c#$as "e seDa$i/aci2n%
7o"as tienen acti>i"a" in'i)itoria so)re BM3s, $as c#a$es a s# >e/ son mo$?c#$as
in'i)itorias%
III- M&LE%5LA' !E%E(#&!A'
La ma*ora "e $os receptores est&n #)ica"os en $a s#per!icie "e $a c?$#$a, mientras 1#e
otros, para mo$?c#$as so$#)$es en $pi"os .esteroi"es, retinoi"es * $a 'ormona tiroi"ea0
est&n #)ica"os en e$ citop$asma%
Los receptores en $a s#per!icie "e $a c?$#$a tienen #n "ominio e-trace$#$ar, otro
transce$#$ar * otro intrace$#$ar% E$ "ominio e-trace$#$ar contiene #na /ona "e #ni2n .e$
receptor0 para $os ligandos, 1#e tpicamente son #na 'ormona, #na citocina o #n !actor
"e crecimiento%
C#an"o e$ $igan"o se #ne a$ receptor, pro>oca #n cam)io en $a con!ormaci2n "e$
"ominio citop$asm&tico%
Los Receptores "e mem)rana son "e "os tipos:
aE $os 1#e presentan acti>i"a" intrnseca proteinasa% E:emp$os son $os !actores "e
crecimiento !i)ro)$&stico .<F<s0 en $os c#a$es e$ "ominio intrace$#$ar posee
acti>i"a" tirosincinasa% Otro e:emp$o, $os receptores para $os !actores "e
crecimiento trans!ormante )eta, pero s# "ominio intrace$#$ar contiene acti>i"a"
serinaHtreoninacinasa%
)E $os 1#e #ti$i/an #n sistema "e seg#n"o mensa:ero 1#e acti>a $as protenas
cinasa en e$ citop$asma% En este caso e$ receptor se #ne a #n $igan"o
.ne#rotransmisor, p?pti"o, 'ormona, !actor "e crecimiento0 * $#ego #na serie "e
pasos interme"ios son re1#eri"os para $a acti>aci2n "e $as protena cinasas%
Notc' es #n receptor 1#e es #n e:emp$o "e este seg#n"o tipo "e receptores%
La >a De$taENotc' es #na >a m#* importante * se e-p$ica a contin#aci2n%
Notc' es e$ receptor
La protena Notc' es #n 'etero"mero% En )io$oga #n "mero es #na protena
comp#esta por "os s#)#ni"a"es% En #n 'omo"mero $as "os s#)#ni"a"es son
i"?nticas * en #n 'etero"mero $as "os #ni"a"es son "i!erentes%
La protena receptora Notc' se e-tien"e a tra>?s "e $a mem)rana ce$#$ar%
A tra>?s "e este receptor se #ne a c?$#$as 1#e e-presan en s# s#per!icie .en s#s
mem)ranas ce$#$ares0 $as protenas Delta: 'errate o Eagged%
Se re1#iere p#es contacto estrec'o entre $as "os c?$#$as%
La #ni2n protena B Notc' 'ace 1#e #na porci2n citop$asm&tica "e Notc' se
"espren"a% Una proteasa "e$ citop$asma rompe esta parte "e Notc'
La parte "espren"i"a se #na a #n !actor "e transcripci2n $$ama"o De$te-, e$
comp$e:o as !orma"o pasa a$ n6c$eo "e $a c?$#$a * se acti>a $a e-presi2n g?nica%
En e$ interior "e$ n6c$eo se #ne a otra partc#$a $$ama"a ;s#presor o! 'air$ess= *
"e esta !orma este n#e>o comp$e:o sir>e "e <actor "e transcripci2n e$ c#a$ se #ne
a$ ADN en #n sitio $$ama"o ;En'ancer o! Sp$it=% E$ pro"#cto "e este gen es otro
!actor "e transcripci2n 1#e a s# >e/ reg#$a otros genes% Este tiene #na in!$#encia
in'i)itoria, reprime $a e-presi2n "e genes%
Notc' es importante en $a "i!erenciaci2n "e $as ne#ronas%
I"- #!AN'D5%%I>N DE LA 'E<AL
Es #n proceso comp$e:o% Inicia con $a #ni2n "e $a mo$?c#$a "e seDa$i/aci2n a$
receptor * esto origina #n cam)io en $a con!ormaci2n intrace$#$ar "e$ receptor%
Esto "esenca"ena #na serie "e reacciones en e$ citop$asma c#*a !#nci2n es $$e>ar
$a seDa$ a$ n6c$eo "e $a c?$#$a, en "on"e in!$#*e en $a e-presi2n "e #n gen%
Es com6n 'a)$ar "e estas >as "e trans"#cci2n "e seDa$ como $inea$es, pero en
rea$i"a" $as >as "e trans"#cci2n "e seDa$ son #na >er"a"era re", s#:etas a #na
gran >arie"a" "e estm#$os mo"#$a"ores% +a* >arias >as "e trans"#cci2n "e
seDa$%
Los miem)ros "e $a !ami$ia "e$ !actor "e crecimiento "e $os !i)ro)$astos .<F<0
se #nen a #n receptor "e $a >a "e $a tirocina cinasa% L#ego "e s# #ni2n a$
receptor #na protena F, cerca a$ receptor en e$ citop$asma res#$ta acti>a"a, * "a
$#gar a #na serie "e reacciones intracitop$asm&ticas, 1#e inician con RAS $#ego
RA<, $#ego MA3 cinasa 1#e termina con ErJ 1#e pasa a$ n6c$eo "e $a c?$#$a e
interact6a con otros !actores "e transcripci2n%
Los miem)ros "e $a !ami$ia "e$ !actor "e trans!ormaci2n )eta .7F< )eta0 se #nen
a #n receptor serinaHtreonina cinasa II, 1#e !orma #n comp$e:o con e$ receptor I
como $o i$#stra $a !ig#ra% Esto acti>a #na >a "omina"a por $as protenas Sma"%
+a* "os tipos "e protenas Sma" .RESma" * CoESma"0 1#e se "imeri/an *
entran a$ n6c$eo% E$ "imero Sma" se #ne a #n co!actor * entonces es capa/ "e
com)inarse con a$g6n e$emento reg#$a"or "e$ ADN%
La >a Cnt es comp$e:a% 3rimero $a mo$?c#$a Cnt se #ne a s# receptor en $a
s#per!icie "e $a c?$#$a, $$ama"o <ri//$e"% <ri//$e" interact6a con $a protena en e$
citop$asma $$ama"a Dis'e>e$e", se con!orma as #n comp$e:o "e >arias
mo$?c#$as $$ama"o e$ Comp$e:o "e Destr#cci2n, e$ a#sencia "e Cnt ca#sa $a
"egra"aci2n "e #na protena $$ama"a Beta catenina% En presencia "e Cnt, )eta
catenina no es "estr#i"a * entonces pasa a$ n6c$eo, en "on"e !orma comp$e:os
con otros !actores "e transcripci2n para "eterminar $a e-presi2n "e #n gen%
Otra "escripci2n "e $as >as "e seDa$i/aci2n:
Pa "e trans"#cci2n:
Molcula sealiadora
Un receptor, "ic'o receptor tiene:
Dominio e-trace$#$ar
Dominio transmem)ranario
Dominio citop$asm&tico
Uni2n $igan"o B receptor
+a* acti>i"a" en/im&tica "e$ receptor, $a "e #na cinasa
Q#e es capa/ "e !os!ori$ar otras protenas #san"o A73 como
s#)strato
La casca"a "e acti>aci2n "e protenas termina acti>an"o #n <7
Un e:emp$o: E$ receptor acti>a"o, act6a >a protenas F .protenas 1#e se #nen a
g#anosinaEtri!os!ato * a g#anosinaE"i!os!ato0, 1#e estim#$a $a en/ima e!ectora
.e:emp$o a"eni$ato cic$asa0 para con>ertir $as mo$?c#$as prec#rsoras en seg#n"os
mensa:eros% Dos seg#n"os mensa:eros signi!icati>os son e$ a"enosinE
mono!os!ato cc$ico * e$ inosnEtri!os!ato m&s "iaci$g$icero$% A contin#aci2n, e$
seg#n"o mensa:ero acti>a $as proteincinasas citop$asm&ticas 1#e in"#cen $a
!os!ori$aci2n .aDa"en gr#pos !os!ato0 en $as protenas "iana, acti>&n"o$as o
inacti>&n"o$as% 3#e"e 'a)er otros pasos pero "esp#?s "e esto oc#rre e$ paso "e $a
mo$?c#$a acti>a"a a$ n6c$eo, * se pro"#ce #n e!ecto so)re $a transcripci2n "e$
DNA%
"- A%ID& !E#IN&I%&
Meta)o$ito "e $a >itamina A% Pitamina 1#e $$ega a$ em)ri2n como retino$%
E$ retino$ se acop$a a #na protena "e #ni2n * a s# >e/ se a"'iere a receptores
espec!icos en $a s#per!icie "e $a c?$#$a% Entra en e$ citop$asma * es $i)era"o "e
este comp$e:o "on"e se #ne a #na prote7na de unin al retinol celular
3%!1(?40 En e$ citop$asma, e$ retino$ to"o B trans es con>erti"o
2Iarngea2Iamente primero a retina$ to"o B trans * $#ego en &ci"o retinoico
to"o trans, 1#e es e$ retinoi"e con acti>i"a" )io$2gica m&s potente% +a* "os
protenas, CRB3 * CRAB3 3prote7na de unin al Fcido retinoico celular4 1#e
reg#$an $a canti"a" "e retinoi"es 1#e a$can/an e$ n6c$eo% Una >e/ $i)era"o a
partir "e CRAB3, entra en e$ n6c$eo, "on"e se #ne a #n 'etero"mero constit#i"o
por #n miem)ro "e $a !ami$ia "e$ receptor del Fcido retinoico 3!A!4 al)a: -eta
o gama * Retinoi" @ receptor "e $a !ami$ia a$!a, )eta o gama% Este comp$e:o
!orma"o por &ci"o retinoico m&s e$ 'etero"imero a$ ;e$emento "e$ resp#esta "e$
&ci"o retinoico= en e$ ADN% .P?ase $a !ig#ra0 * act6a como #n !actor "e
transcripci2n contro$an"o e$ pro"#cto "e #n gen%
E$ &ci"o retinoico es pro"#ci"o * #ti$i/a"o en regiones $oca$es espec!icas
"#rante $a etapa prenata$ * $a posnata$%
Una "e s#s !#nciones conoci"as en $as !ases inicia$es "e$ "esarro$$o son a$g#nos
genes +o- .+o-)E1 por e:emp$o0, canti"a"es ins#!icientes o e-cesi>as "e &ci"o
retinoico p#e"e "ar $#gar a trastornos gra>es en $a organi/aci2n "e$
rom)enc?!a$o * "e $a cresta ne#ra$ 2Iarngea%
"I- M&LE%5LA' DE AD+E'I>N
7res son $as m&s importantes
1E Ca"erinas
2E IgECAMs
4E NECAMs
4E Integrinas
Los $igan"os "e $a matri/ e-trace$#$ar interact6an con receptores "e $as
c?$#$as >ecinas%
Matri/ e-trace$#$ar: !orma"a por mo$?c#$as como co$&geno, proteog$#canos
.s#$!ato "e con"roitina, &ci"o 'ia$#r2nico, etc0 * g$#coprotenas como
!i)ronectina * $aminina%
Los receptores 1#e #nen a $as mo$?c#$as e-trace$#$ares, como !i)ronectina *
$aminina se $$aman integrinas0
Estos receptores integran a $as m2$ec#$as "e $a matri/ e-trace$#$ar en #na
ma1#inaria citoes1#e$?tica B se !orma #n sistema "e migraci2n para $as
c?$#$as meso"?rmicas%
GENE' G5E IN#E!"IENEN EN EL DE'A!!&LL& ; %AN%E!
A$g#nos "e $os genes 1#e participan en e$ "esarro$$o em)rionario #na >e/ 1#e m#tan
"an $#gar a "i>ersos c&nceres% +a* "os gr#pos "e genes imp$ica"os en esto:
1E Los protooncogenes: p#e"en con>ertirse en oncogenes 1#e son $os ca#santes
rea$es "e $a pro$i!eraci2n ce$#$ar "escontro$a"a% Los protooncogenes "irigen $a
!ormaci2n norma$ "e mo$?c#$as tan "i>ersas como ciertos !actores "e
crecimiento, receptores "e !actores "e crecimiento, protenas "e seDa$i/aci2n "e
mem)rana * citop$asm&ticas * !actores "e transcripci2n%
In"#cen $a !ormaci2n t#mora$ a tra>?s "e mecanismos "e ganancia "e !#nci2n%
2E Los genes s#presores t#mora$es: 1#e s#e$en act#ar $imitan"o $a !rec#encia "e $as
"i>isiones ce$#$ares% Los a$e$os recesi>os, con per"i"a "e $a !#nci2n "e estos
genes no p#e"en s#primir $a "i>isi2n ce$#$ar, $o 1#e 'ace 1#e apare/can
"i>isiones incontro$a"as en po)$aciones ce$#$ares "e!ini"as%R
4E