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1. Homeobox Genes and Craniofacial Development
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INDIAN DENTAL ACADEMY
Leader in continuing dental education
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2. Homeobox Genes andHomeobox Genes and
Craniofacial DevelopmentCraniofacial Development
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3. IntroductionIntroduction
The advent of molecular biology has allowedThe advent of molecular biology has allowed
biologists to uncover, characterize, andbiologists to uncover, characterize, and
ultimately manipulate the genes that make upultimately manipulate the genes that make up
the genome of the fertilized egg. We can nowthe genome of the fertilized egg. We can now
study how genes and proteins operate withinstudy how genes and proteins operate within
their natural habitats. This is significantlytheir natural habitats. This is significantly
furthering our understanding of the fundamentalfurthering our understanding of the fundamental
principles of development, how genes controlprinciples of development, how genes control
cell behavior and, thus, how they determine thecell behavior and, thus, how they determine the
pattern and form of an embryo.pattern and form of an embryo.
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4. Without this knowledge of gene activityWithout this knowledge of gene activity
and the relevant cellular signaland the relevant cellular signal
transduction pathways, elucidating thetransduction pathways, elucidating the
mechanisms that control developmentmechanisms that control development
would be impossible. These advances arewould be impossible. These advances are
now influencing medicine and clinicalnow influencing medicine and clinical
genetics with almost daily progression ingenetics with almost daily progression in
explaining the basis of a multitude ofexplaining the basis of a multitude of
congenital malformations, andcongenital malformations, and
abnormalities.abnormalities.
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5. By virtue of the structure itself, generation of theBy virtue of the structure itself, generation of the
craniofacial complex is a process that requirescraniofacial complex is a process that requires
considerable organization. The vertebrate headconsiderable organization. The vertebrate head
is a composite structure whose formation beginsis a composite structure whose formation begins
early in development, as the brain is beginningearly in development, as the brain is beginning
to form. Central to the development of a head isto form. Central to the development of a head is
the concept of segmentation, manifest in thethe concept of segmentation, manifest in the
hindbrain and branchial arch systems.hindbrain and branchial arch systems.
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6. In conjunction with migrating neural crestIn conjunction with migrating neural crest
cells these systems will give rise to muchcells these systems will give rise to much
of the head and neck and their associated,of the head and neck and their associated,
individualized compartments.individualized compartments.
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7. It is now becoming clear that theIt is now becoming clear that the
molecular control of embryonicmolecular control of embryonic
morphology resides at the level of themorphology resides at the level of the
gene, in particular, within families of genesgene, in particular, within families of genes
that encode transcription factors capablethat encode transcription factors capable
of regulating downstream geneof regulating downstream gene
transcription.transcription.
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8. The Role of the Neural CrestThe Role of the Neural Crest
The neural crest is a highly pluripotent cellThe neural crest is a highly pluripotent cell
population that plays a critical role in thepopulation that plays a critical role in the
development of the vertebrate head.development of the vertebrate head.
Unlike most parts of the body, the facialUnlike most parts of the body, the facial
mesenchyme is derived principally frommesenchyme is derived principally from
the neural crest and not the mesoderm ofthe neural crest and not the mesoderm of
the embryonic third germ layerthe embryonic third germ layer
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9. In mammals, neural crest cells are formedIn mammals, neural crest cells are formed
during neurulation when cells at theduring neurulation when cells at the
margins of the neural folds undergo anmargins of the neural folds undergo an
epithelial to mesenchymal transitionepithelial to mesenchymal transition
following an inductive interaction betweenfollowing an inductive interaction between
neural plate and presumptive ectoderm.neural plate and presumptive ectoderm.
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10. Neural crest cells migrate extensivelyNeural crest cells migrate extensively
throughout the embryo in four overlappingthroughout the embryo in four overlapping
domains (cephalic, trunk, sacral, anddomains (cephalic, trunk, sacral, and
cardiac), in the developing head thecardiac), in the developing head the
cephalic neural crest migrates from thecephalic neural crest migrates from the
posterior midbrain and hindbrain regionsposterior midbrain and hindbrain regions
into the branchial arch system.into the branchial arch system.
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12. The ectomesenchymal neural crest cellsThe ectomesenchymal neural crest cells
then interact with epithelial andthen interact with epithelial and
mesodermal cell populations presentmesodermal cell populations present
within the arches, leading to the formationwithin the arches, leading to the formation
of craniofacial bones, cartilages andof craniofacial bones, cartilages and
connective tissuesconnective tissues
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14. Derivatives of cranial neural crestDerivatives of cranial neural crest
Nervous systemNervous system
Neurons, includingNeurons, including Sensory gangliaSensory ganglia
Sympathetic ganglia (V, VII, IX, X)Sympathetic ganglia (V, VII, IX, X)
Parasympathetic ganglia of neckParasympathetic ganglia of neck
Neuroglial cellsNeuroglial cells
Schwann cellsSchwann cells
Skeletal systemSkeletal system
Branchial arch cartilagesBranchial arch cartilages
Bones, includingBones, including MaxillaMaxilla
MandibleMandible
PalatinePalatine
Facial complexFacial complex
Cranial vaultCranial vaultwww.indiandentalacademy.comwww.indiandentalacademy.com
15. Connective tissuesConnective tissues
Connective tissue component of:Connective tissue component of: Cranial musculatureCranial musculature
AdenohypophysisAdenohypophysis
Lingual glandsLingual glands
ThymusThymus
Thyroid and parathyroidsThyroid and parathyroids
Vascular and dermal smooth musclesVascular and dermal smooth muscles
Odontoblasts and pulp of the teethOdontoblasts and pulp of the teeth
Corneal endothelium and stromaCorneal endothelium and stroma
Melanocytes and melanoporesMelanocytes and melanopores
Pigment cellsPigment cells
Epidermal pigment cellsEpidermal pigment cells
Secretory cellsSecretory cells
Carotid body Type I cellsCarotid body Type I cells
Calcitonin producing cells of ultimobranchial bodyCalcitonin producing cells of ultimobranchial bodywww.indiandentalacademy.comwww.indiandentalacademy.com
16. Patterning the Branchial Regions ofPatterning the Branchial Regions of
the Headthe Head
Fundamental to the development of theFundamental to the development of the
craniofacial complex is the central nervouscraniofacial complex is the central nervous
system (CNS). The CNS arises from thesystem (CNS). The CNS arises from the
neural plate, a homogenous sheet ofneural plate, a homogenous sheet of
epithelial cells that forms the dorsalepithelial cells that forms the dorsal
surface of the gastrula stage embryo.surface of the gastrula stage embryo.
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17. As the neural plate rolls up along its APAs the neural plate rolls up along its AP
axis to form the neural tube the enlargedaxis to form the neural tube the enlarged
anterior end partitions into three vesicles.anterior end partitions into three vesicles.
These vesicles are the primordia of theThese vesicles are the primordia of the
developing forebrain (prosencephalon),developing forebrain (prosencephalon),
midbrain (mesencephalon), and hindbrainmidbrain (mesencephalon), and hindbrain
(rhombencephalon).(rhombencephalon).
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18. It is the rhombencephalic derived neuralIt is the rhombencephalic derived neural
crest that will give rise to the majority ofcrest that will give rise to the majority of
the branchial arch mesenchyme. It isthe branchial arch mesenchyme. It is
clear, therefore, that the neural crestclear, therefore, that the neural crest
derived from the hindbrain is essential forderived from the hindbrain is essential for
normal formation of the face and neck.normal formation of the face and neck.
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19. The hindbrain itself is known to be aThe hindbrain itself is known to be a
segmented structure composed of eightsegmented structure composed of eight
subunits called rhombomeres (Lumsdensubunits called rhombomeres (Lumsden
and Keynes, 1989). Rhombomeres areand Keynes, 1989). Rhombomeres are
important segmental units of organization,important segmental units of organization,
which have distinct morphologicalwhich have distinct morphological
properties that vary with a two-segmentproperties that vary with a two-segment
periodicity.periodicity.
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20. The neural crest cells that migrate andThe neural crest cells that migrate and
form the bulk of the facial mesenchymeform the bulk of the facial mesenchyme
arise from the same axial level of neuralarise from the same axial level of neural
tube as the rhombomeres whosetube as the rhombomeres whose
neurones will ultimately innervate thatneurones will ultimately innervate that
mesenchyme.mesenchyme.
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21. Neural crest cells destined for the firstNeural crest cells destined for the first
branchial arch migrate essentially frombranchial arch migrate essentially from
rhombomeres 1 and 2, whilst those for therhombomeres 1 and 2, whilst those for the
second and third arches migrate fromsecond and third arches migrate from
rhombomeres 4 and 6, respectively. Therhombomeres 4 and 6, respectively. The
even numbered rhombomeres (2, 4, andeven numbered rhombomeres (2, 4, and
6) contain the exit points for cranial nerves6) contain the exit points for cranial nerves
V, VII, and IX, nerves that will innervateV, VII, and IX, nerves that will innervate
branchial arches 1, 2, and 3.branchial arches 1, 2, and 3.
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22. Homeobox GenesHomeobox Genes
Edward Lewis was the first person toEdward Lewis was the first person to
identify the Homeotic Genes in the fly,identify the Homeotic Genes in the fly,
which help in controlling thewhich help in controlling the
developmental response of a group ofdevelopmental response of a group of
cells along the body’s antero-posteriorcells along the body’s antero-posterior
axis.axis.
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23. In the early 1980s biologists beganIn the early 1980s biologists began
searching for genes containing thesearching for genes containing the
DrosophilaDrosophila homeobox in vertebrates,homeobox in vertebrates,
reasoning that the highly conservedreasoning that the highly conserved
nature of the homeobox betweennature of the homeobox between
homeotic genes might have beenhomeotic genes might have been
preserved during evolution. If this was thepreserved during evolution. If this was the
case, then these genes might play a keycase, then these genes might play a key
role during vertebrate developmentrole during vertebrate development
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24. In a landmark evolutionary survey, usingIn a landmark evolutionary survey, using
DNA from a variety of species, it wasDNA from a variety of species, it was
shown that the homeobox is not confinedshown that the homeobox is not confined
to insects, but is also found in vertebratesto insects, but is also found in vertebrates
(McGinnis(McGinnis et alet al., 1984). Considering., 1984). Considering
humans are separated from flies byhumans are separated from flies by
around 600 million years this conservationaround 600 million years this conservation
was astounding.was astounding.
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25. The first vertebrate homeobox was rapidlyThe first vertebrate homeobox was rapidly
cloned in the frogcloned in the frog Xenopus levisXenopus levis (Carrasco(Carrasco
et alet al., 1984) and this was soon followed by., 1984) and this was soon followed by
the mouse (McGinnisthe mouse (McGinnis et alet al., 1984).., 1984).
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27. These vertebrate genes were calledThese vertebrate genes were called HoxHox
genes, and as more were cloned itgenes, and as more were cloned it
became clear that during the course ofbecame clear that during the course of
evolution considerable duplication andevolution considerable duplication and
divergence had occurred from the originaldivergence had occurred from the original
ancestral cluster (Duboule and Dollé,ancestral cluster (Duboule and Dollé,
1989; Graham1989; Graham et alet al., 1989).., 1989).
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28. In the mouse and human genomes thereIn the mouse and human genomes there
are 39are 39 HoxHox genes related togenes related to DrosophilaDrosophila
homeotic genes. Thesehomeotic genes. These HoxHox genes aregenes are
arranged in four clusters (instead of one inarranged in four clusters (instead of one in
the fly) on four different chromosomes;the fly) on four different chromosomes;
Hoxa-dHoxa-d in mice andin mice and HOXA-DHOXA-D in manin man
(Scott, 1992).(Scott, 1992).
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30. In animals these genes- Homeobox Genes- areIn animals these genes- Homeobox Genes- are
considered for pattern formation, throughconsidered for pattern formation, through
interaction of their products with regulatoryinteraction of their products with regulatory
elements in cellular DNA to activate or inhibitelements in cellular DNA to activate or inhibit
downstream genes. These are considereddownstream genes. These are considered
‘Master Genes’ of head and face with a‘Master Genes’ of head and face with a
prominent control over patterning , induction,prominent control over patterning , induction,
programmed cell death and epithelial-programmed cell death and epithelial-
mesenchymal interaction during craniofacialmesenchymal interaction during craniofacial
development.development.
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31. The expression of these genes can be seenThe expression of these genes can be seen
along the dorsal axis within the central nervousalong the dorsal axis within the central nervous
system from the anterior region of the hindbrainsystem from the anterior region of the hindbrain
through the length of the spinal cord. As thethrough the length of the spinal cord. As the
neural crest cells migrate from the rhombomeresneural crest cells migrate from the rhombomeres
into specific branchial arches, it retains ainto specific branchial arches, it retains a
specific Hox code, which specifies form andspecific Hox code, which specifies form and
pattern of different derived regions of the headpattern of different derived regions of the head
and neck.and neck.
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33. The neural crest cells destined for the firstThe neural crest cells destined for the first
branchial arch does not express Hox genesbranchial arch does not express Hox genes
related to homeotic homeobox but relies on itsrelated to homeotic homeobox but relies on its
subfamilies. The subfamilies of Hox genes,subfamilies. The subfamilies of Hox genes,
which are of particular interest in craniofacialwhich are of particular interest in craniofacial
patterning and morphogenesis include- musclepatterning and morphogenesis include- muscle
segment(Msx), Distal less(Dlx),segment(Msx), Distal less(Dlx),
orthodenticle(Otx), Goosecoid(Gsc), Barorthodenticle(Otx), Goosecoid(Gsc), Bar
class(Barx), paired-related(Prx, SHOT) and LIMclass(Barx), paired-related(Prx, SHOT) and LIM
homeobox.homeobox.
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34. The expression of these genes is mediatedThe expression of these genes is mediated
through two main groups of regulatory proteins-through two main groups of regulatory proteins-
Growth factor family and steroid/thyroid/retinoicGrowth factor family and steroid/thyroid/retinoic
acid super family.acid super family.
The vehicle through which Hox gene informationThe vehicle through which Hox gene information
is expressed for the regulation of growth processis expressed for the regulation of growth process
include fibroblast growth factor(FGF),include fibroblast growth factor(FGF),
Transforming growth factor α and β, and boneTransforming growth factor α and β, and bone
morphogenetic proteins 4 (BMP4).morphogenetic proteins 4 (BMP4).
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35. The Muscle Segment (Msx)The Muscle Segment (Msx)
The vertebrateThe vertebrate MsxMsx genes were initiallygenes were initially
cloned from mice and identified ascloned from mice and identified as
homologous to thehomologous to the DrosophilaDrosophila musclemuscle
segment homeoboxsegment homeobox gene (gene (mshmsh))
Subsequently,Subsequently, MsxMsx genes have beengenes have been
isolated from a variety of organisms,isolated from a variety of organisms,
including ascidians, sea urchin,including ascidians, sea urchin,
zebrafish, ,frogs, birds, and humans.zebrafish, ,frogs, birds, and humans.
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36. These genes are primarily expressed inThese genes are primarily expressed in
regions that give rise to highly derived orregions that give rise to highly derived or
vertebrate specific structures like skull,vertebrate specific structures like skull,
teeth, limbs, axial and appendicularteeth, limbs, axial and appendicular
skeleton and tripartite brain. Vertebrateskeleton and tripartite brain. Vertebrate
have three Msx- Msx1, Msx2 and Msx3 ofhave three Msx- Msx1, Msx2 and Msx3 of
which only the first two are involved inwhich only the first two are involved in
craniofacial patterning andcraniofacial patterning and
morphogenesis.morphogenesis.
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37. The earliest restricted distribution ofThe earliest restricted distribution of Msx1Msx1 duringduring
tooth development in mice is evident aroundtooth development in mice is evident around
E11.0 in the dental mesenchyme at the laminaE11.0 in the dental mesenchyme at the lamina
stage, and the expression increases in thestage, and the expression increases in the
condensing dental mesenchyme at the budcondensing dental mesenchyme at the bud
stage. At the morphogenetic cap stages both thestage. At the morphogenetic cap stages both the
dental papilla and follicle expressdental papilla and follicle express Msx1Msx1
maximally. The expression begins to level offmaximally. The expression begins to level off
prior to the differentiation of the odontoblastsprior to the differentiation of the odontoblasts
and ameloblasts.and ameloblasts.
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39. In the late stages of tooth morphogenesis,In the late stages of tooth morphogenesis,
Msx1Msx1 expression is clearly absent from theexpression is clearly absent from the
root sheath epithelium and is rather weakroot sheath epithelium and is rather weak
in the dental pulp. Hence it appears thatin the dental pulp. Hence it appears that
Msx1Msx1 does not support rootdoes not support root
morphogenesis in the developing tooth.morphogenesis in the developing tooth.
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40. Apart from the tooth,Apart from the tooth, Msx1Msx1 expression has beenexpression has been
examined in the developing palate. Reports of aexamined in the developing palate. Reports of a
weak, diffuse expression ofweak, diffuse expression of Msx1Msx1 in the palatalin the palatal
mesenchyme provided the first evidence thatmesenchyme provided the first evidence that
Msx1Msx1 may have a direct role in palatemay have a direct role in palate
development. A more detailed analysis by Zhangdevelopment. A more detailed analysis by Zhang
et al has reported thatet al has reported that Msx1Msx1 expression in theexpression in the
palatal mesenchyme is confined to the anteriorpalatal mesenchyme is confined to the anterior
portion of the developing palatal shelves.portion of the developing palatal shelves.
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42. MSX2MSX2 expression is detectable by 7.5 weeks ofexpression is detectable by 7.5 weeks of
human embryonic development. In humans, thehuman embryonic development. In humans, the
precursors of the orofacial skeleton such as theprecursors of the orofacial skeleton such as the
mandibular and maxillary bones, Meckel'smandibular and maxillary bones, Meckel's
cartilage, and tooth germs all expresscartilage, and tooth germs all express MSX2MSX2. At. At
the bud stage of developing tooth germ,the bud stage of developing tooth germ, MSX2MSX2 isis
detectable in the vestibular lamina, and both thedetectable in the vestibular lamina, and both the
dental epithelium and mesenchyme.dental epithelium and mesenchyme.
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43. Later in development,Later in development, MSX2MSX2 expression isexpression is
lost from the dental mesenchyme but islost from the dental mesenchyme but is
seen in the enamel knot and vestibularseen in the enamel knot and vestibular
epithelium of the cap stage tooth. In mice,epithelium of the cap stage tooth. In mice,
Msx2Msx2 expression is continuous in theexpression is continuous in the
molar and incisor tooth germs. Unlike themolar and incisor tooth germs. Unlike the
developing incisors, the molar tooth germsdeveloping incisors, the molar tooth germs
show asymmetric distribution ofshow asymmetric distribution of Msx2Msx2 atat
all developmental stages.all developmental stages.
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44. Contrary toContrary to Msx1Msx1, whose expression is, whose expression is
confined to the mesenchyme throughoutconfined to the mesenchyme throughout
tooth development,tooth development, Msx2Msx2 expression canexpression can
be detected in both the epithelial andbe detected in both the epithelial and
mesenchymal compartments of themesenchymal compartments of the
developing tooth germs. The earliestdeveloping tooth germs. The earliest
indication of asymmetric expression is itsindication of asymmetric expression is its
buccal distribution seen within thebuccal distribution seen within the
invaginating dental lamina of molar toothinvaginating dental lamina of molar tooth
germs.germs.
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45. At the cap stage,At the cap stage, Msx2Msx2 expression isexpression is
prominently seen in the components of theprominently seen in the components of the
enamel organ (the enamel navel, septumenamel organ (the enamel navel, septum
and knot) as well as the inner enameland knot) as well as the inner enamel
epithelium. With the onset of the bellepithelium. With the onset of the bell
stage,stage, Msx2Msx2 expression is lost from theexpression is lost from the
inner enamel epithelium as theyinner enamel epithelium as they
differentiate into the ameloblasts.differentiate into the ameloblasts.
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46. Instead, strong expression ofInstead, strong expression of Msx2Msx2 isis
detected in the odontoblasts and thedetected in the odontoblasts and the
subodontoblastic regions of the dentalsubodontoblastic regions of the dental
papilla. Thus, the spatial and temporalpapilla. Thus, the spatial and temporal
expression ofexpression of Msx1Msx1 andand Msx2Msx2 genesgenes
appear to correlate with crucial aspects ofappear to correlate with crucial aspects of
craniofacial morphogenesis.craniofacial morphogenesis.
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47. Differential expression of these genes withDifferential expression of these genes with
those of Dlx confers positional identity onthose of Dlx confers positional identity on
arch ectomesenchyme, particularly in thearch ectomesenchyme, particularly in the
dental field. Msx 1 is restricted to the distaldental field. Msx 1 is restricted to the distal
mesenchyme , which ultimately formmesenchyme , which ultimately form
chondrogenic condensations and Msx2 ischondrogenic condensations and Msx2 is
mainly concentrated in non-chondrogenicmainly concentrated in non-chondrogenic
regions.regions.
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48. Targeted gene disruption of Msx1 gene in miceTargeted gene disruption of Msx1 gene in mice
affects the shape of several calvarial andaffects the shape of several calvarial and
chondrogenic bones, both derived from firstchondrogenic bones, both derived from first
branchial arch. The effects can be seen as cleftbranchial arch. The effects can be seen as cleft
palate associated with loss of palatine shelves inpalate associated with loss of palatine shelves in
both maxillary and palatine bones, maxillary andboth maxillary and palatine bones, maxillary and
mandibular hypoplasia and highly penetrantmandibular hypoplasia and highly penetrant
arrest of tooth formation at the bud stage ofarrest of tooth formation at the bud stage of
development.development.
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50. MSX1 mutations have been identified in threeMSX1 mutations have been identified in three
families with autosomal-dominant toothfamilies with autosomal-dominant tooth
agenesis. To test the hypothesis that MSX1agenesis. To test the hypothesis that MSX1
mutations are a common cause of congenitalmutations are a common cause of congenital
tooth agenesis, Lidral and Reising (2002)tooth agenesis, Lidral and Reising (2002)
screened 92 affected individuals, representingscreened 92 affected individuals, representing
82 nuclear families, for mutations, using single-82 nuclear families, for mutations, using single-
strand conformation analysis. A Met61Lysstrand conformation analysis. A Met61Lys
substitution was found in two siblings from asubstitution was found in two siblings from a
large family with autosomal-dominant toothlarge family with autosomal-dominant tooth
agenesis.agenesis.
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51. Complete concordance of the mutation withComplete concordance of the mutation with
tooth agenesis was observed in the extendedtooth agenesis was observed in the extended
family. The siblings had a pattern of severe toothfamily. The siblings had a pattern of severe tooth
agenesis, suggesting that mutations in MSX1agenesis, suggesting that mutations in MSX1
are responsible for a specific pattern of inheritedare responsible for a specific pattern of inherited
tooth agenesis. Supporting this theory, notooth agenesis. Supporting this theory, no
mutations were found in more common cases ofmutations were found in more common cases of
incisor or premolar agenesis, indicating thatincisor or premolar agenesis, indicating that
these have a different etiology.these have a different etiology.
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52. Mutations in the MSX1 homeobox geneMutations in the MSX1 homeobox gene
are associated with non-syndromic cleftare associated with non-syndromic cleft
palate and tooth agenesis in humans.palate and tooth agenesis in humans.
Zhang , Song Y, Zhao X, Zhang X, FerminZhang , Song Y, Zhao X, Zhang X, Fermin
C, Chen Y, used Msx1-deficient mice as aC, Chen Y, used Msx1-deficient mice as a
model system that exhibits severemodel system that exhibits severe
craniofacial abnormalities, including cleftcraniofacial abnormalities, including cleft
secondary palate and lack of teeth, tosecondary palate and lack of teeth, to
study the genetic regulation of mammalianstudy the genetic regulation of mammalian
palatogenesis.palatogenesis.
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53. They found that Msx1 expression wasThey found that Msx1 expression was
restricted to the anterior of the first upperrestricted to the anterior of the first upper
molar site in the palatal mesenchyme andmolar site in the palatal mesenchyme and
that Msx1 was required for the expressionthat Msx1 was required for the expression
of Bmp4 and Bmp2 in the mesenchymeof Bmp4 and Bmp2 in the mesenchyme
and Shh in the medial edge epitheliumand Shh in the medial edge epithelium
(MEE) in the same region of developing(MEE) in the same region of developing
palate.palate.
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54. In vivo and in vitro analyses indicated thatIn vivo and in vitro analyses indicated that
the cleft palate seen in Msx1 mutantsthe cleft palate seen in Msx1 mutants
resulted from a defect in cell proliferationresulted from a defect in cell proliferation
in the anterior palatal mesenchyme ratherin the anterior palatal mesenchyme rather
than a failure in palatal fusion.than a failure in palatal fusion.
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55. Transgenic expression of human Bmp4 drivenTransgenic expression of human Bmp4 driven
by the mouse Msx1 promoter in the Msx1(-/-)by the mouse Msx1 promoter in the Msx1(-/-)
palatal mesenchyme rescued the cleft palatepalatal mesenchyme rescued the cleft palate
phenotype and neonatal lethality. Associatedphenotype and neonatal lethality. Associated
with the rescue of the cleft palate was awith the rescue of the cleft palate was a
restoration of Shh and Bmp2 expression, as wellrestoration of Shh and Bmp2 expression, as well
as a return of cell proliferation to the normalas a return of cell proliferation to the normal
levels. Ectopic Bmp4 appears to bypass thelevels. Ectopic Bmp4 appears to bypass the
requirement for Msx1 and functions upstream ofrequirement for Msx1 and functions upstream of
Shh and Bmp2 to support palatal development.Shh and Bmp2 to support palatal development.
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56. Msx1 thus controls a genetic hierarchyMsx1 thus controls a genetic hierarchy
involving BMP and Shh signals thatinvolving BMP and Shh signals that
regulates the growth of the anterior regionregulates the growth of the anterior region
of palate during mammalianof palate during mammalian
palatogenesis. These findings providepalatogenesis. These findings provide
insights into the cellular and molecularinsights into the cellular and molecular
etiology of the non-syndromic cleftingetiology of the non-syndromic clefting
associated with Msx1 mutations.associated with Msx1 mutations.
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57. Distal less (Dlx)Distal less (Dlx)
Like Msx, these genes are also primarilyLike Msx, these genes are also primarily
expressed in regions that give rise toexpressed in regions that give rise to
highly derived or vertebrate specifichighly derived or vertebrate specific
structures. Dlx1 and Dlx2 are expressedstructures. Dlx1 and Dlx2 are expressed
throughout first and second branchialthroughout first and second branchial
arches whereas expression of Dlx3, Dlx4,arches whereas expression of Dlx3, Dlx4,
Dlx5 and Dlx6 are restricted more distallyDlx5 and Dlx6 are restricted more distally
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58. Dlx homeobox genes are mammalianDlx homeobox genes are mammalian
homologues of the Drosophila Distal-lesshomologues of the Drosophila Distal-less
(Dll) gene. The Dlx/Dll gene family is of(Dll) gene. The Dlx/Dll gene family is of
ancient origin and appears to play a role inancient origin and appears to play a role in
appendage development in essentially allappendage development in essentially all
species in which it has been identified. Inspecies in which it has been identified. In
Drosophila, Dll is expressed in the distalDrosophila, Dll is expressed in the distal
portion of the developing appendages andportion of the developing appendages and
is critical for the development of distalis critical for the development of distal
structures.structures.
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59. In addition, human Dlx5 and Dlx6In addition, human Dlx5 and Dlx6
homeobox genes have been identified ashomeobox genes have been identified as
possible candidate genes for thepossible candidate genes for the
autosomal dominant form of the split-autosomal dominant form of the split-
hand/split-foot malformation (SHFM), ahand/split-foot malformation (SHFM), a
heterogeneous limb disorderheterogeneous limb disorder
characterized by missing central digits andcharacterized by missing central digits and
claw-like distal extremities.claw-like distal extremities.
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60. Targeted inactivation of Dlx5 and Dlx6Targeted inactivation of Dlx5 and Dlx6
genes in mice results in severegenes in mice results in severe
craniofacial, axial, and appendicularcraniofacial, axial, and appendicular
skeletal abnormalities, leading to perinatalskeletal abnormalities, leading to perinatal
lethality. Dlx/Dll gene products have beenlethality. Dlx/Dll gene products have been
shown to be critical regulators ofshown to be critical regulators of
mammalian limb development, asmammalian limb development, as
combined loss-of-function mutationscombined loss-of-function mutations
phenocopy Split hand/ split footphenocopy Split hand/ split foot
malformation.malformation.
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61. Msx-Dlx interactionMsx-Dlx interaction
The Msx expression is restricted to cellsThe Msx expression is restricted to cells
that are proliferating or dying whereas Dlxthat are proliferating or dying whereas Dlx
expression is found in regions undergoingexpression is found in regions undergoing
differentiation or are capable of doing so.differentiation or are capable of doing so.
Accordingly Msx and Dlx proteins appearAccordingly Msx and Dlx proteins appear
to have opposite transcription factors- Msxto have opposite transcription factors- Msx
proteins function as transcriptionalproteins function as transcriptional
repressos while Dlx proteins arerepressos while Dlx proteins are
activators.activators.
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62. Role of Msx-Dlx in tooth developmentRole of Msx-Dlx in tooth development
Msx and Dlx genes participate in toothMsx and Dlx genes participate in tooth
development by reciprocal epithelial-development by reciprocal epithelial-
mesenchymal interaction. As themesenchymal interaction. As the
epithelium of the prospective oral cavityepithelium of the prospective oral cavity
thickens to form dental lamina, thethickens to form dental lamina, the
expression of Msx2 localizes. Activation ofexpression of Msx2 localizes. Activation of
Msx1, Msx2, Dlx1,Dlx2 in dentalMsx1, Msx2, Dlx1,Dlx2 in dental
mesenchyme in response to BMP4 andmesenchyme in response to BMP4 and
FGF signals form the overlying epithelium.FGF signals form the overlying epithelium.
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63. The BMP4 induction of Msx1 expressionThe BMP4 induction of Msx1 expression
and subsequent Msx dependent activationand subsequent Msx dependent activation
and maintenance of BMP4 expression inand maintenance of BMP4 expression in
dental mesenchyme are key steps indental mesenchyme are key steps in
conferring the odontogenic potential toconferring the odontogenic potential to
these tissues.these tissues.
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64. The failure of tooth development toThe failure of tooth development to
progress past the early bud stage in Msx1progress past the early bud stage in Msx1
-/- (mutant) mice and earlier arrest at-/- (mutant) mice and earlier arrest at
laminar stage in the absence of both Msx1laminar stage in the absence of both Msx1
and Msx2 emphasize the role of theseand Msx2 emphasize the role of these
genes in mediating signaling events.genes in mediating signaling events.
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65. Mice lacking Dlx1 and Dlx2 show noMice lacking Dlx1 and Dlx2 show no
defects on tooth development but Dlx1 -/-;defects on tooth development but Dlx1 -/-;
Dlx2 -/- compound mutant mice lackingDlx2 -/- compound mutant mice lacking
molars indicate sensitivity to Dlx1 andmolars indicate sensitivity to Dlx1 and
Dlx2 protein 2 levels in limited subset ofDlx2 protein 2 levels in limited subset of
teeth. In humans, a point mutation in Msx1teeth. In humans, a point mutation in Msx1
homeobox result in agenesis of secondhomeobox result in agenesis of second
premolars and third molars in affectedpremolars and third molars in affected
individuals.individuals.
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66. Goosecoid (Gsc)Goosecoid (Gsc)
This homeobox containing gene orThis homeobox containing gene or
transcription factor, encode a paired liketranscription factor, encode a paired like
homeoprotein and is expressed duringhomeoprotein and is expressed during
gastrulation in regions of the embryo withgastrulation in regions of the embryo with
axial patterning activity. At late stages ofaxial patterning activity. At late stages of
embryogenesis, Gsc is expressed inembryogenesis, Gsc is expressed in
craniofacial regions, ventral body wall andcraniofacial regions, ventral body wall and
limbs.limbs.
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67. Rivera-Perez (1995) showed that GscRivera-Perez (1995) showed that Gsc
mutants mice died soon after birth withmutants mice died soon after birth with
multiple craniofacial defects and rib cagemultiple craniofacial defects and rib cage
malformations. Mutant mice have beenmalformations. Mutant mice have been
shown to exhibit a hypoplastic mandibleshown to exhibit a hypoplastic mandible
with lack of coronoid and angular processwith lack of coronoid and angular process
along with several defects of other bonesalong with several defects of other bones
like maxilla, palatine bones and pterygoidlike maxilla, palatine bones and pterygoid
plates.plates.
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68. Otx gene (Otx1 and Otx2)Otx gene (Otx1 and Otx2)
From experiments in mice it is clear thatFrom experiments in mice it is clear that
prior to gastrulation Otx2 is expressed inprior to gastrulation Otx2 is expressed in
epiblast and visceral endoderm and itsepiblast and visceral endoderm and its
expression becomes restricted to anteriorexpression becomes restricted to anterior
parts of all three germ layers, as theparts of all three germ layers, as the
primitive streak is formed.primitive streak is formed.
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69. According to Matsuo et al (1995), OtxAccording to Matsuo et al (1995), Otx
homozygous mutants fail to develophomozygous mutants fail to develop
structures anterior to rhombomere 3. thestructures anterior to rhombomere 3. the
Otx2 in cranial neural crest cells wasOtx2 in cranial neural crest cells was
evidenced by otocephaly due to defect inevidenced by otocephaly due to defect in
these cells of Otx2 homozygous mutants.these cells of Otx2 homozygous mutants.
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70. The Bar ClassThe Bar Class
The Bar class of homeobox genes consisting ofThe Bar class of homeobox genes consisting of
Barx1 and Barx2, contains protein meant forBarx1 and Barx2, contains protein meant for
protein-protein interaction to regulate theprotein-protein interaction to regulate the
function of homeodomain. Both bar class genesfunction of homeodomain. Both bar class genes
are expressed during development of centralare expressed during development of central
nervous system and peripheral nervous system.nervous system and peripheral nervous system.
They are expressed in telencephalon,They are expressed in telencephalon,
diencehalon, mesencephalon, hind brain anddiencehalon, mesencephalon, hind brain and
spinal cord and in cranial and dorsal rootspinal cord and in cranial and dorsal root
ganglia.ganglia.
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71. Expression of Barx 2 is most prominent inExpression of Barx 2 is most prominent in
mantle layer, in which post mitotic neuronsmantle layer, in which post mitotic neurons
are located, the palatal floor and dorsalare located, the palatal floor and dorsal
root ganglia, mutations of which canroot ganglia, mutations of which can
produce clefts of secondary palate.produce clefts of secondary palate.
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72. The Paired related gene (Prx andThe Paired related gene (Prx and
SHOT)SHOT)
Prx1 and Prx2 are closely relatedPrx1 and Prx2 are closely related
members of Prx family of homeoboxmembers of Prx family of homeobox
genes. Prx1 in combination with Prx2 isgenes. Prx1 in combination with Prx2 is
essential to stabilize and maintain cellessential to stabilize and maintain cell
fates in craniofacial mesenchyme.fates in craniofacial mesenchyme.
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73. Mutation experiments in mice elicited theMutation experiments in mice elicited the
role of Prx1 in dental mesenchyme of allrole of Prx1 in dental mesenchyme of all
tooth germs and are considered importanttooth germs and are considered important
in tooth development. Ten Berge et alin tooth development. Ten Berge et al
found defects in external, middle and innerfound defects in external, middle and inner
ear, reduction or loss of skull bones, aear, reduction or loss of skull bones, a
reduced or sometimes cleft of thereduced or sometimes cleft of the
mandible and limb abnormalities inmandible and limb abnormalities in
Prx1/Prx2 double mutantsPrx1/Prx2 double mutants
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74. Another paired related homeobox gene-Another paired related homeobox gene-
SHOT- with two different isomers SHOTaSHOT- with two different isomers SHOTa
and SHOTb are considered homologousand SHOTb are considered homologous
to human SHOX and mouse OG-12. theto human SHOX and mouse OG-12. the
transcription factors encoded by this genetranscription factors encoded by this gene
are expressed in the developing aorta,are expressed in the developing aorta,
female genitalia, diencephalons, nasalfemale genitalia, diencephalons, nasal
capsule, palate, eyelid and limb.capsule, palate, eyelid and limb.
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75. SHOT was mapped to humanSHOT was mapped to human
chromosome 3q25-q26. this chromosomalchromosome 3q25-q26. this chromosomal
region is involved in development ofregion is involved in development of
Cornelia-de- Hange syndrome,Cornelia-de- Hange syndrome,
characterized by mental retardation,characterized by mental retardation,
microcephaly, cleft palate, abnormallymicrocephaly, cleft palate, abnormally
situated eyelids, nose and ear deformities,situated eyelids, nose and ear deformities,
as well as heart and lung defects.as well as heart and lung defects.
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76. The short stature homeobox gene SHOXThe short stature homeobox gene SHOX
is associated with idiopathic short statureis associated with idiopathic short stature
in humans, as seen in Turner syndromein humans, as seen in Turner syndrome
and Leri-Weill dyschondrosteosis, whileand Leri-Weill dyschondrosteosis, while
little is known about its close relativelittle is known about its close relative
SHOX2.SHOX2.
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77. There is restricted expression of Shox2There is restricted expression of Shox2
in the anterior domain of the secondaryin the anterior domain of the secondary
palate in mice and humans. Shox2-/-palate in mice and humans. Shox2-/-
mice develop an incomplete cleft that ismice develop an incomplete cleft that is
confined to the anterior region of theconfined to the anterior region of the
palate, an extremely rare type of cleftingpalate, an extremely rare type of clefting
in humans. The Shox2-/- palatalin humans. The Shox2-/- palatal
shelves initiate, grow and elevateshelves initiate, grow and elevate
normally, but the anterior region fails tonormally, but the anterior region fails to
contact and fuse at the midline, owingcontact and fuse at the midline, owing
to altered cell proliferation andto altered cell proliferation and
apoptosis, leading to incomplete cleftingapoptosis, leading to incomplete clefting
within the presumptive hard palate.within the presumptive hard palate.
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78. Tissue recombination and bead implantationTissue recombination and bead implantation
experiments have revealed that signals fromexperiments have revealed that signals from
the anterior palatal epithelium are responsiblethe anterior palatal epithelium are responsible
for the restricted mesenchymal Shox2for the restricted mesenchymal Shox2
expression. BMP activity is necessary but notexpression. BMP activity is necessary but not
sufficient for the induction of palatal Shox2sufficient for the induction of palatal Shox2
expression. Studies demonstrate an intrinsicexpression. Studies demonstrate an intrinsic
requirement for Shox2 in palatogenesis, andrequirement for Shox2 in palatogenesis, and
support the idea that palatogenesis issupport the idea that palatogenesis is
differentially regulated along thedifferentially regulated along the
anteroposterior axis. Also, the fusion of theanteroposterior axis. Also, the fusion of the
posterior palate can occur independently ofposterior palate can occur independently of
fusion in the anterior palate.fusion in the anterior palate.
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79. The LIM homeobox genesThe LIM homeobox genes
The Lhx8 transcripts are expressed inThe Lhx8 transcripts are expressed in
neural crest derived ectomesenchymeneural crest derived ectomesenchyme
of the first branchial arch and also inof the first branchial arch and also in
developing tooth during the postnataldeveloping tooth during the postnatal
period. The role of Lhx8 gene in palatalperiod. The role of Lhx8 gene in palatal
development has been shown and indevelopment has been shown and in
homozygous mutant mice for Lhx8homozygous mutant mice for Lhx8
gene, the formation and elevation ofgene, the formation and elevation of
palatal shelves appeared to proceedpalatal shelves appeared to proceed
normally but failed to make contact andnormally but failed to make contact and
fuse.fuse.
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80. The cleft palate is a common finding inThe cleft palate is a common finding in
mice carrying mutations of Lhx8 gene andmice carrying mutations of Lhx8 gene and
can be considered as a potential gene forcan be considered as a potential gene for
human cleft palate also.human cleft palate also.
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81. ConclusionsConclusions
The study of gene function continues toThe study of gene function continues to
demonstrate how an understanding of thedemonstrate how an understanding of the
basic science behind development canbasic science behind development can
lead to advances of direct relevance to thelead to advances of direct relevance to the
clinician. Many human syndromes andclinician. Many human syndromes and
genetic abnormalities have now beengenetic abnormalities have now been
attributed to defects in individual genes.attributed to defects in individual genes.
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82. Mutations in genes that influence any ofMutations in genes that influence any of
these processes would causethese processes would cause
craniofacial abnormalities, such ascraniofacial abnormalities, such as
facial clefting and craniosynostosis,facial clefting and craniosynostosis,
which are among the most frequentwhich are among the most frequent
congenital birth defects in humans It iscongenital birth defects in humans It is
only by understanding the processesonly by understanding the processes
involved during normal developmentinvolved during normal development
that we can begin to unravel thethat we can begin to unravel the
mechanisms that are responsible formechanisms that are responsible for
various craniofacial malformations.various craniofacial malformations.
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89. Thank youThank you
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