Homeobox genes (2) /certified fixed orthodontic courses by Indian dental academy

Homeobox GenesHomeobox Genes
INDIAN DENTAL ACADEMY
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Self AssemblySelf Assembly
• Human analogies for almost everything inHuman analogies for almost everything in
nature.nature.
• Heart – pumpHeart – pump
• Eye – cameraEye – camera
• Natural selection – trial and errorNatural selection – trial and error
• Genes – recipiesGenes – recipies
• Brain – wires(axons) switches(synapses)Brain – wires(axons) switches(synapses)
and so on.and so on.

• One of the most remarkable, beautiful &One of the most remarkable, beautiful &
bizarre thing that mother nature achievesbizarre thing that mother nature achieves
without apparent difficulty is something forwithout apparent difficulty is something for
which we have no human analogy at all:which we have no human analogy at all:
the development of a human body from anthe development of a human body from an
undifferentiated blob called aundifferentiated blob called a fertilizedfertilized
eggegg..

• Something, somewhere must be imposingSomething, somewhere must be imposing
a pattern of increasing detail upon the egga pattern of increasing detail upon the egg
as it grows and develops. There must be aas it grows and develops. There must be a
plan.plan.
• That imposer of detail must be within theThat imposer of detail must be within the
egg itself.egg itself.
• How can the egg make a pattern withoutHow can the egg make a pattern without
starting with one?starting with one?
• Theories of preformation.Theories of preformation.

• A Miniature homunculus of a man withinA Miniature homunculus of a man within
the human sperm.the human sperm.
• Aristotle:Aristotle: preformation merely postponespreformation merely postpones
the problem, for how did the homunculusthe problem, for how did the homunculus
get its shape.get its shape.
• William BatesonWilliam Bateson – 1– 1stst
conjectured that “allconjectured that “all
organisms ae made from an orderly seriesorganisms ae made from an orderly series
of parts or segments, and coined the termof parts or segments, and coined the term
HOMEOSISHOMEOSIS for it.for it.
• 1970s: It all revolves around genes which1970s: It all revolves around genes which
do indeed contain a plan.do indeed contain a plan.

• One large cluster of these developmentalOne large cluster of these developmental
genes lie close to the middle ofgenes lie close to the middle of
chromosome 12.chromosome 12.
• Fertilized eggFertilized egg→→embryoembryo→undifferentiated→undifferentiated
blob.blob.
• 2 asymmetries develop – a head tail axis2 asymmetries develop – a head tail axis
and a front back axis.and a front back axis.
• In fruit flies – these asymmetries areIn fruit flies – these asymmetries are
established by the mother.established by the mother.
• In mice and humans - ?In mice and humans - ?

• These asymmetries are almost certainlyThese asymmetries are almost certainly
chemical.chemical.
• Each cell can taste the soup inside itself.Each cell can taste the soup inside itself.
• Knowing where you are is just theKnowing where you are is just the
beginning.beginning.
• Knowing what you have to do once youKnowing what you have to do once you
are there is wholly different problem.are there is wholly different problem.
• Genes that control this process are calledGenes that control this process are called
asas HOMEOTICHOMEOTIC genes.genes.
• Totally decentralised process.Totally decentralised process.

• Homeotic GeneHomeotic Gene ::
A gene that affects embryo developmentA gene that affects embryo development
by specifying the character of a bodyby specifying the character of a body
segment.segment.
• E.g. in Antennapedia, a gene that, whenE.g. in Antennapedia, a gene that, when
mutated, causes a fruitfly to grow a leg inmutated, causes a fruitfly to grow a leg in
place of an antenna.place of an antenna.
• A gene containing a 180-base-pairA gene containing a 180-base-pair
segment (the “homeobox”) that encodes asegment (the “homeobox”) that encodes a
protein domain involved in binding to (andprotein domain involved in binding to (and
thus regulating the expression of)thus regulating the expression of) DNADNA..

• Since their discovery in 1983, homeoboxSince their discovery in 1983, homeobox
genes, and the proteins they encode (thegenes, and the proteins they encode (the
homeodomain proteins), have turned outhomeodomain proteins), have turned out
to play important roles in theto play important roles in the
developmental processes.developmental processes.
• Crucial roles in embryogenesis.Crucial roles in embryogenesis.
• Many homeobox genes are not homeoticMany homeobox genes are not homeotic
genes.genes.
• All homeotic genes are genes forAll homeotic genes are genes for
switching other genes on or off.switching other genes on or off.

• At the level of embryology we are glorifiedAt the level of embryology we are glorified
flies.flies.
• Evolutionary implication – we descendedEvolutionary implication – we descended
from common ancestor with flies whichfrom common ancestor with flies which
used the same way of defining the patternused the same way of defining the pattern
of the embryo more than 530 million yearsof the embryo more than 530 million years
ago.ago.

• It was once thought that head was aIt was once thought that head was a
vertebrate speciality – a whole set of newvertebrate speciality – a whole set of new
genes for building a speciallygenes for building a specially
encephalised front end, complete withencephalised front end, complete with
brain.brain.
• Now we know 2 pairs of genes involved inNow we know 2 pairs of genes involved in
making the brain in the mousemaking the brain in the mouse OtxOtx(1 & 2)(1 & 2)
and Emxand Emx(1 & 2), are pretty near(1 & 2), are pretty near
equivalents of 2 genes that are expressedequivalents of 2 genes that are expressed
in the development of the head end of thein the development of the head end of the
fruit fly.fruit fly.

• 8 homeobox genes are linked in a cluster on one8 homeobox genes are linked in a cluster on one
Drosophila chromosome.Drosophila chromosome.
• All of them:All of them:
encode transcription factors .encode transcription factors .
each with a DNA-binding homeodomain .each with a DNA-binding homeodomain .
act in sequential zones of the embryo in theact in sequential zones of the embryo in the
same ordersame order that they occur on thethat they occur on the
chromosome .chromosome .
• the entire cluster is designatedthe entire cluster is designated HOM-CHOM-C ..
• Only genes in the HOX cluster can be namedOnly genes in the HOX cluster can be named
Hox genes.Hox genes.

• Gehring’s colleague Eddie de RobertisGehring’s colleague Eddie de Robertis
went fishing among the genes of frog,went fishing among the genes of frog,
mice.mice.
• He found the same 180 base string – theHe found the same 180 base string – the
homeobox.homeobox.
• 4 hox clusters in mice, laid similar to that4 hox clusters in mice, laid similar to that
in fruit fly – end to end with the headin fruit fly – end to end with the head
genes 1genes 1stst
and the tail genes last.and the tail genes last.

• Mice and humans have 4Mice and humans have 4 HoxHox clusters (aclusters (a
total of 39 genes in humans) located ontotal of 39 genes in humans) located on
four different chromosomes.four different chromosomes.
• In mice:In mice: HoxAHoxA,, HoxBHoxB,, HoxCHoxC,, HoxDHoxD
• In humans:In humans: HOXAHOXA,, HOXBHOXB,, HOXCHOXC,, HOXDHOXD
• All genes show some sequence homologyAll genes show some sequence homology
to each other .to each other .
• But very strong sequence homology to theBut very strong sequence homology to the
equivalent genes in Drosophila e.g.equivalent genes in Drosophila e.g.
HoxB7HoxB7 differs fromdiffers from AntpAntp at only two aminoat only two amino
acids.acids.

UltrabithoraxUltrabithorax ((UbxUbx))

Double mutation in theDouble mutation in the
UltrabithoraxUltrabithorax genegene

• UltrabithoraxUltrabithorax ((UbxUbx) is a ") is a "selector geneselector gene".".
• Selector genes are genes that regulateSelector genes are genes that regulate
(turning on or off) the expression of other(turning on or off) the expression of other
genes.genes.
• Thus selector genes act as "Thus selector genes act as "mastermaster
switchesswitches" in development." in development.
• Selector genes encodeSelector genes encode
transcription factorstranscription factors ..

• Once a selector gene turns "on" in certain cellsOnce a selector gene turns "on" in certain cells
of the embryo, it remains "on" in all the cellsof the embryo, it remains "on" in all the cells
derived from those cells.derived from those cells.
• Those cells become irrevocably committed toThose cells become irrevocably committed to
carrying out the genetic program leading to thecarrying out the genetic program leading to the
formation of a leg or wing.formation of a leg or wing.
• AntennapediaAntennapedia ((AntpAntp))
• Sequences of mouseSequences of mouse small eyessmall eyes gene andgene and
DrosophilaDrosophila eyelesseyeless genes are so similar thatgenes are so similar that
the mouse gene can substitute for eyelessthe mouse gene can substitute for eyeless
when introduced into Drosophila.when introduced into Drosophila.

So, like the genes of theSo, like the genes of the HoxHox clusters,clusters,
• DrosophilaDrosophila eyelesseyeless and mouseand mouse smallsmall
eyeseyes have retained, through millions ofhave retained, through millions of
years of independent evolution, theiryears of independent evolution, their
function of assigning particular positions infunction of assigning particular positions in
the embryo where certain structuresthe embryo where certain structures
should be built, butshould be built, but
• the structures actually built depend on athe structures actually built depend on a
different set of genes specific for adifferent set of genes specific for a
particular species.particular species.

• In flies –In flies – decapentaplegicdecapentaplegic is dorsalising;is dorsalising;
short gastrulationshort gastrulation is ventralising.is ventralising.
• In mice and humans 2 very similar genesIn mice and humans 2 very similar genes
–– BMP4BMP4 ((decapentaplegicdecapentaplegic) is ventralising;) is ventralising;
chordinchordin ((short gastrulationshort gastrulation) is dorsalising.) is dorsalising.
• This means that arthropods andThis means that arthropods and
vertebrates are upside-down versions ofvertebrates are upside-down versions of
each others.each others.
• They in ancient past had a commonThey in ancient past had a common
ancestor.ancestor.

• One of the descendents took to walkingOne of the descendents took to walking
on its stomach while the other took toon its stomach while the other took to
walking on its back.walking on its back.
• Dorsalising and ventralising genesDorsalising and ventralising genes
predate the split between the 2 lineages.predate the split between the 2 lineages.
• Etienne Geoffroy St Hilaire, Frenchman 1Etienne Geoffroy St Hilaire, Frenchman 1stst
guessed this fact in 1822, from observingguessed this fact in 1822, from observing
embryos in different animals.embryos in different animals.
• CNS of insect – lies along its belly; whileCNS of insect – lies along its belly; while
that of human being lies along its back.that of human being lies along its back.

• Similarity between genes are so close thatSimilarity between genes are so close that
geneticists knock out a gene in fly bygeneticists knock out a gene in fly by
deliberately mutating it, and replacing it bydeliberately mutating it, and replacing it by
genetic engineering with equivalent genegenetic engineering with equivalent gene
from a human being and grow a normalfrom a human being and grow a normal
fly.fly.
• This technique is known as geneticThis technique is known as genetic
resque.resque.
• Genes are like chunks of software thatGenes are like chunks of software that
can run on any system.can run on any system.

• Even after 530 million years of separation,Even after 530 million years of separation,
our computers can recognize fly’sour computers can recognize fly’s
software and vice versa.software and vice versa.
• Extra hox genes(13) in the cluster inExtra hox genes(13) in the cluster in
humans and mice than in fly(8).humans and mice than in fly(8).
• Post anal tails; spines that go on well pastPost anal tails; spines that go on well past
the anuses.the anuses.
• Tails shrank – these genes areTails shrank – these genes are
presumably somewhat silent in uspresumably somewhat silent in us
compared with their equivalents in mice.compared with their equivalents in mice.

• Genes of particular interest in craniofacialGenes of particular interest in craniofacial
development include:development include:
-Hox group-Hox group
-Msx1 and Msx2 (muscle segment-Msx1 and Msx2 (muscle segment
homeobox)homeobox)
-Dlx (distalles)-Dlx (distalles)
-Otx (orthodontical)-Otx (orthodontical)
-Gsc (goosccoid)-Gsc (goosccoid)
-Shh (sonic hedgehog)-Shh (sonic hedgehog)

• The regulatory molecules in theThe regulatory molecules in the
mesenchyme such as FGF, EGF, TGFmesenchyme such as FGF, EGF, TGF
and BMPs are the vehicles through whichand BMPs are the vehicles through which
the homeobox gene information isthe homeobox gene information is
expressed in the coordination of cellexpressed in the coordination of cell
migration and subsequent cell interactionmigration and subsequent cell interaction
that regulate growth.that regulate growth.

• The expression of theThe expression of the HoxHox genes isgenes is
evident in the hindbrain, but it is alsoevident in the hindbrain, but it is also
evident in the neural crest cells thatevident in the neural crest cells that
populate the branchial arches, providingpopulate the branchial arches, providing
further evidence that hindbrainfurther evidence that hindbrain
segmentation has direct effects onsegmentation has direct effects on
craniofacial patterning.craniofacial patterning.
• Two gene families — the ephrin/EphTwo gene families — the ephrin/Eph
receptors and the Hox transcription factorsreceptors and the Hox transcription factors
are essential for establishingare essential for establishing
compartments and imposing segmentalcompartments and imposing segmental
identity.identity.

• More recent experiments have shown thatMore recent experiments have shown that
the morphogenetic programme andthe morphogenetic programme and HoxHox
gene expression are not irreversiblygene expression are not irreversibly
committed but can show plasticity.committed but can show plasticity.
• Some genes and critical factors involvedSome genes and critical factors involved
in tooth development are – homeoboxin tooth development are – homeobox
genes, hedgehog genes, BMPs, FGFs etc.genes, hedgehog genes, BMPs, FGFs etc.

• MSX gene – involved in tooth formationMSX gene – involved in tooth formation
(epithelial mesenchymal tissue(epithelial mesenchymal tissue
interactions).interactions).
• MSX1 is expressed in migrating neuralMSX1 is expressed in migrating neural
crest cells & in mesenchymal cells ofcrest cells & in mesenchymal cells of
dental papilla and follicles.dental papilla and follicles.
• Three MSX genes in mammals – MSX1-3.Three MSX genes in mammals – MSX1-3.
• Msx2 is expressed in osteogenic tissuesMsx2 is expressed in osteogenic tissues
of the mandible and maxilla.of the mandible and maxilla.
• Msx2 mutation – autosomal dominantMsx2 mutation – autosomal dominant
craniosynostosis – premature closure ofcraniosynostosis – premature closure of
the cranial sutures.the cranial sutures.

• Location of Msx2 mRNA in the sutures.Location of Msx2 mRNA in the sutures.
• Msx2 expression may be related to theMsx2 expression may be related to the
regulation of the progression of theregulation of the progression of the
osteogenesis and closing of the sutures.osteogenesis and closing of the sutures.
• Studies tie Msx expression to boneStudies tie Msx expression to bone
development and osteoblasticdevelopment and osteoblastic
differentiation.differentiation.
• Osteocalcin gene, expressed uniquely inOsteocalcin gene, expressed uniquely in
osteoblastic cells, is dependent on bindingosteoblastic cells, is dependent on binding
of Msx gene products.of Msx gene products.

• Expression of Msx2 studied in osteoblastsExpression of Msx2 studied in osteoblasts
of the periosteum of the mature mandibleof the periosteum of the mature mandible
and maxilla.and maxilla.
• Expression of Msx2 is a clear markerExpression of Msx2 is a clear marker
differentiating the mature mandibular anddifferentiating the mature mandibular and
maxillary alveolar bones from other bonesmaxillary alveolar bones from other bones
of the adult skeleton.of the adult skeleton.
• Msx1 knockout in mice caused – clefting,Msx1 knockout in mice caused – clefting,
aberration in tooth development, missingaberration in tooth development, missing
teeth and deficiency of alveolar bones.teeth and deficiency of alveolar bones.

• Msx2 knock out – multiple inductiveMsx2 knock out – multiple inductive
failures and early death.failures and early death.
• Combination Msx1 and 2 knock out –Combination Msx1 and 2 knock out –
severe aberration of development of thesevere aberration of development of the
skeleton and some other organs, severeskeleton and some other organs, severe
skeletal deficiencies in calvaria and teethskeletal deficiencies in calvaria and teeth
and alveolar bone.and alveolar bone.

• Orthodontic implication – bone turn overOrthodontic implication – bone turn over
rate and bone induction.rate and bone induction.
• Lhx gene – lim homeobox 8(Lhx8)Lhx gene – lim homeobox 8(Lhx8)
implicated in craniofacial deformities.implicated in craniofacial deformities.

• Barx gene – Bar class homeobox 1(Barx1)Barx gene – Bar class homeobox 1(Barx1)
is expressed within the ectomesenchymeis expressed within the ectomesenchyme
of 1of 1stst
branchial arch.branchial arch.
• Barx1 expression is localized to theBarx1 expression is localized to the
mesenchymal regions around themesenchymal regions around the
developing molars.developing molars.
• Could be associated with facial and dentalCould be associated with facial and dental
anomalies.anomalies.

• Dlx gene – Distal less homeobox genes.Dlx gene – Distal less homeobox genes.
Expressed in migrating neural crest cellsExpressed in migrating neural crest cells
and in the 1and in the 1stst
branchial arch.branchial arch.
• Dlx2 isolated in Mesenchymal cellsDlx2 isolated in Mesenchymal cells
restricted to the proximal regions fromrestricted to the proximal regions from
where the future molar teeth will develop.where the future molar teeth will develop.
• PAX gene – paired box homeotic gene.PAX gene – paired box homeotic gene.
Modify transcriptional activities ofModify transcriptional activities of
downstream genes.downstream genes.

• Hedgehog genes – Sonic hedgehogHedgehog genes – Sonic hedgehog
gene(Shh) is expressed in the epithelialgene(Shh) is expressed in the epithelial
thickenings of the tooth forming regions.thickenings of the tooth forming regions.
• Shh along with BMP4 determines theShh along with BMP4 determines the
positions of the future forming toothpositions of the future forming tooth
germs.germs.
• Shh is necessary for initiation of toothShh is necessary for initiation of tooth
development, epithelial signaling anddevelopment, epithelial signaling and
cuspal morphogenesis.cuspal morphogenesis.

• Gli Zinc transcription factors along withGli Zinc transcription factors along with
Shh is also imperative for tooth formation.Shh is also imperative for tooth formation.
• Gli1, Gli2 & Gli3, play a vital role in toothGli1, Gli2 & Gli3, play a vital role in tooth
development.development.
• Mutant Gli2 resulted in formation ofMutant Gli2 resulted in formation of
abnormal incisors.abnormal incisors.

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