Homeobox Genes and Craniofacial Development
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Introduction The advent of molecular biology has allowed biologists to uncover, characterize, and ultimately manipulate the genes that make up the genome of the fertilized egg. We can now study how genes and proteins operate within their natural habitats. This is significantly furthering our understanding of the fundamental principles of development, how genes control cell behavior and, thus, how they determine the pattern and form of an embryo.
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Without this knowledge of gene activity and the relevant cellular signal transduction pathways, elucidating the mechanisms that control development would be impossible. These advances are now influencing medicine and clinical genetics with almost daily progression in explaining the basis of a multitude of congenital malformations, and abnormalities. www.indiandentalacademy.com0
By virtue of the structure itself, generation of the craniofacial complex is a process that requires considerable organization. The vertebrate head is a composite structure whose formation begins early in development, as the brain is beginning to form. Central to the development of a head is the concept of segmentation, manifest in the hindbrain and branchial arch systems.
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In conjunction with migrating neural crest cells these systems will give rise to much of the head and neck and their associated, individualized compartments.
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It is now becoming clear that the molecular control of embryonic morphology resides at the level of the gene, in particular, within families of genes that encode transcription factors capable of regulating downstream gene transcription.
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The Role of the Neural Crest The neural crest is a highly pluripotent cell population that plays a critical role in the development of the vertebrate head. Unlike most parts of the body, the facial mesenchyme is derived principally from the neural crest and not the mesoderm of the embryonic third germ layer
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In mammals, neural crest cells are formed during neurulation when cells at the margins of the neural folds undergo an epithelial to mesenchymal transition following an inductive interaction between neural plate and presumptive ectoderm.
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Neural crest cells migrate extensively throughout the embryo in four overlapping domains (cephalic, trunk, sacral, and cardiac), in the developing head the cephalic neural crest migrates from the posterior midbrain and hindbrain regions into the branchial arch system.
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The ectomesenchymal neural crest cells then interact with epithelial and mesodermal cell populations present within the arches, leading to the formation of craniofacial bones, cartilages and connective tissues
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Derivatives of cranial neural crest Nervous system Neurons, including
Sensory ganglia Sympathetic ganglia (V, VII, IX, X) Parasympathetic ganglia of neck Neuroglial cells Schwann cells
Skeletal system Branchial arch cartilages Bones, including
Maxilla Mandible Palatine Facial complex www.indiandentalacademy.com0 Cranial vault
Connective tissues Connective tissue component of:
Cranial musculature Adenohypophysis Lingual glands Thymus Thyroid and parathyroids
Vascular and dermal smooth muscles Odontoblasts and pulp of the teeth Corneal endothelium and stroma Melanocytes and melanopores Pigment cells Epidermal pigment cells Secretory cells Carotid body Type I cells Calcitonin producing cells of ultimobranchial body www.indiandentalacademy.com0
Patterning the Branchial Regions of the Head Fundamental to the development of the craniofacial complex is the central nervous system (CNS). The CNS arises from the neural plate, a homogenous sheet of epithelial cells that forms the dorsal surface of the gastrula stage embryo.
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As the neural plate rolls up along its AP axis to form the neural tube the enlarged anterior end partitions into three vesicles. These vesicles are the primordia of the developing forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon).
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It is the rhombencephalic derived neural crest that will give rise to the majority of the branchial arch mesenchyme. It is clear, therefore, that the neural crest derived from the hindbrain is essential for normal formation of the face and neck.
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The hindbrain itself is known to be a segmented structure composed of eight subunits called rhombomeres (Lumsden and Keynes, 1989). Rhombomeres are important segmental units of organization, which have distinct morphological properties that vary with a two-segment periodicity. www.indiandentalacademy.com0
The neural crest cells that migrate and form the bulk of the facial mesenchyme arise from the same axial level of neural tube as the rhombomeres whose neurones will ultimately innervate that mesenchyme.
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Neural crest cells destined for the first branchial arch migrate essentially from rhombomeres 1 and 2, whilst those for the second and third arches migrate from rhombomeres 4 and 6, respectively. The even numbered rhombomeres (2, 4, and 6) contain the exit points for cranial nerves V, VII, and IX, nerves that will innervate branchial arches 1, 2, and 3. www.indiandentalacademy.com0
Homeobox Genes Edward Lewis was the first person to identify the Homeotic Genes in the fly, which help in controlling the developmental response of a group of cells along the body’s antero-posterior axis.
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In the early 1980s biologists began searching for genes containing the Drosophila homeobox in vertebrates, reasoning that the highly conserved nature of the homeobox between homeotic genes might have been preserved during evolution. If this was the case, then these genes might play a key role during vertebrate development www.indiandentalacademy.com0
In a landmark evolutionary survey, using DNA from a variety of species, it was shown that the homeobox is not confined to insects, but is also found in vertebrates (McGinnis et al., 1984). Considering humans are separated from flies by around 600 million years this conservation was astounding. www.indiandentalacademy.com0
The first vertebrate homeobox was rapidly cloned in the frog Xenopus levis (Carrasco et al., 1984) and this was soon followed by the mouse (McGinnis et al., 1984).
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These vertebrate genes were called Hox genes, and as more were cloned it became clear that during the course of evolution considerable duplication and divergence had occurred from the original ancestral cluster (Duboule and DollĂŠ, 1989; Graham et al., 1989).
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In the mouse and human genomes there are 39 Hox genes related to Drosophila homeotic genes. These Hox genes are arranged in four clusters (instead of one in the fly) on four different chromosomes; Hoxa-d in mice and HOXA-D in man (Scott, 1992).
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In animals these genes- Homeobox Genes- are considered for pattern formation, through interaction of their products with regulatory elements in cellular DNA to activate or inhibit downstream genes. These are considered ‘Master Genes’ of head and face with a prominent control over patterning , induction, programmed cell death and epithelialmesenchymal interaction during craniofacial development. www.indiandentalacademy.com0
The expression of these genes can be seen along the dorsal axis within the central nervous system from the anterior region of the hindbrain through the length of the spinal cord. As the neural crest cells migrate from the rhombomeres into specific branchial arches, it retains a specific Hox code, which specifies form and pattern of different derived regions of the head and neck.
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The neural crest cells destined for the first branchial arch does not express Hox genes related to homeotic homeobox but relies on its subfamilies. The subfamilies of Hox genes, which are of particular interest in craniofacial patterning and morphogenesis include- muscle segment(Msx), Distal less(Dlx), orthodenticle(Otx), Goosecoid(Gsc), Bar class(Barx), paired-related(Prx, SHOT) and LIM homeobox. www.indiandentalacademy.com0
The expression of these genes is mediated through two main groups of regulatory proteinsGrowth factor family and steroid/thyroid/retinoic acid super family. The vehicle through which Hox gene information is expressed for the regulation of growth process include fibroblast growth factor(FGF), Transforming growth factor ι and β, and bone morphogenetic proteins 4 (BMP4).
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The Muscle Segment (Msx) The vertebrate Msx genes were initially cloned from mice and identified as homologous to the Drosophila muscle segment homeobox gene (msh) Subsequently, Msx genes have been isolated from a variety of organisms, including ascidians, sea urchin, zebrafish, ,frogs, birds, and humans. www.indiandentalacademy.com0
These genes are primarily expressed in regions that give rise to highly derived or vertebrate specific structures like skull, teeth, limbs, axial and appendicular skeleton and tripartite brain. Vertebrate have three Msx- Msx1, Msx2 and Msx3 of which only the first two are involved in craniofacial patterning and morphogenesis. www.indiandentalacademy.com0
The earliest restricted distribution of Msx1 during tooth development in mice is evident around E11.0 in the dental mesenchyme at the lamina stage, and the expression increases in the condensing dental mesenchyme at the bud stage. At the morphogenetic cap stages both the dental papilla and follicle express Msx1 maximally. The expression begins to level off prior to the differentiation of the odontoblasts and ameloblasts.
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In the late stages of tooth morphogenesis, Msx1 expression is clearly absent from the root sheath epithelium and is rather weak in the dental pulp. Hence it appears that Msx1 does not support root morphogenesis in the developing tooth.
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Apart from the tooth, Msx1 expression has been examined in the developing palate. Reports of a weak, diffuse expression of Msx1 in the palatal mesenchyme provided the first evidence that Msx1 may have a direct role in palate development. A more detailed analysis by Zhang et al has reported that Msx1 expression in the palatal mesenchyme is confined to the anterior portion of the developing palatal shelves.
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MSX2 expression is detectable by 7.5 weeks of human embryonic development. In humans, the precursors of the orofacial skeleton such as the mandibular and maxillary bones, Meckel's cartilage, and tooth germs all express MSX2. At the bud stage of developing tooth germ, MSX2 is detectable in the vestibular lamina, and both the dental epithelium and mesenchyme.
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Later in development, MSX2 expression is lost from the dental mesenchyme but is seen in the enamel knot and vestibular epithelium of the cap stage tooth. In mice, Msx2 expression is continuous in the molar and incisor tooth germs. Unlike the developing incisors, the molar tooth germs show asymmetric distribution of Msx2 at all developmental stages. www.indiandentalacademy.com0
Contrary to Msx1, whose expression is confined to the mesenchyme throughout tooth development, Msx2 expression can be detected in both the epithelial and mesenchymal compartments of the developing tooth germs. The earliest indication of asymmetric expression is its buccal distribution seen within the invaginating dental lamina of molar tooth germs. www.indiandentalacademy.com0
At the cap stage, Msx2 expression is prominently seen in the components of the enamel organ (the enamel navel, septum and knot) as well as the inner enamel epithelium. With the onset of the bell stage, Msx2 expression is lost from the inner enamel epithelium as they differentiate into the ameloblasts. www.indiandentalacademy.com0
Instead, strong expression of Msx2 is detected in the odontoblasts and the subodontoblastic regions of the dental papilla. Thus, the spatial and temporal expression of Msx1 and Msx2 genes appear to correlate with crucial aspects of craniofacial morphogenesis.
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Differential expression of these genes with those of Dlx confers positional identity on arch ectomesenchyme, particularly in the dental field. Msx 1 is restricted to the distal mesenchyme , which ultimately form chondrogenic condensations and Msx2 is mainly concentrated in non-chondrogenic regions. www.indiandentalacademy.com0
Targeted gene disruption of Msx1 gene in mice affects the shape of several calvarial and chondrogenic bones, both derived from first branchial arch. The effects can be seen as cleft palate associated with loss of palatine shelves in both maxillary and palatine bones, maxillary and mandibular hypoplasia and highly penetrant arrest of tooth formation at the bud stage of development.
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MSX1 mutations have been identified in three families with autosomal-dominant tooth agenesis. To test the hypothesis that MSX1 mutations are a common cause of congenital tooth agenesis, Lidral and Reising (2002) screened 92 affected individuals, representing 82 nuclear families, for mutations, using singlestrand conformation analysis. A Met61Lys substitution was found in two siblings from a large family with autosomal-dominant tooth agenesis. www.indiandentalacademy.com0
Complete concordance of the mutation with tooth agenesis was observed in the extended family. The siblings had a pattern of severe tooth agenesis, suggesting that mutations in MSX1 are responsible for a specific pattern of inherited tooth agenesis. Supporting this theory, no mutations were found in more common cases of incisor or premolar agenesis, indicating that these have a different etiology.
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Mutations in the MSX1 homeobox gene are associated with non-syndromic cleft palate and tooth agenesis in humans. Zhang , Song Y, Zhao X, Zhang X, Fermin C, Chen Y, used Msx1-deficient mice as a model system that exhibits severe craniofacial abnormalities, including cleft secondary palate and lack of teeth, to study the genetic regulation of mammalian palatogenesis. www.indiandentalacademy.com0
They found that Msx1 expression was restricted to the anterior of the first upper molar site in the palatal mesenchyme and that Msx1 was required for the expression of Bmp4 and Bmp2 in the mesenchyme and Shh in the medial edge epithelium (MEE) in the same region of developing palate. www.indiandentalacademy.com0
In vivo and in vitro analyses indicated that the cleft palate seen in Msx1 mutants resulted from a defect in cell proliferation in the anterior palatal mesenchyme rather than a failure in palatal fusion.
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Transgenic expression of human Bmp4 driven by the mouse Msx1 promoter in the Msx1(-/-) palatal mesenchyme rescued the cleft palate phenotype and neonatal lethality. Associated with the rescue of the cleft palate was a restoration of Shh and Bmp2 expression, as well as a return of cell proliferation to the normal levels. Ectopic Bmp4 appears to bypass the requirement for Msx1 and functions upstream of Shh and Bmp2 to support palatal development.
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Msx1 thus controls a genetic hierarchy involving BMP and Shh signals that regulates the growth of the anterior region of palate during mammalian palatogenesis. These findings provide insights into the cellular and molecular etiology of the non-syndromic clefting associated with Msx1 mutations. www.indiandentalacademy.com0
Distal less (Dlx) Like Msx, these genes are also primarily expressed in regions that give rise to highly derived or vertebrate specific structures. Dlx1 and Dlx2 are expressed throughout first and second branchial arches whereas expression of Dlx3, Dlx4, Dlx5 and Dlx6 are restricted more distally
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Dlx homeobox genes are mammalian homologues of the Drosophila Distal-less (Dll) gene. The Dlx/Dll gene family is of ancient origin and appears to play a role in appendage development in essentially all species in which it has been identified. In Drosophila, Dll is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. www.indiandentalacademy.com0
In addition, human Dlx5 and Dlx6 homeobox genes have been identified as possible candidate genes for the autosomal dominant form of the splithand/split-foot malformation (SHFM), a heterogeneous limb disorder characterized by missing central digits and claw-like distal extremities. www.indiandentalacademy.com0
Targeted inactivation of Dlx5 and Dlx6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. Dlx/Dll gene products have been shown to be critical regulators of mammalian limb development, as combined loss-of-function mutations phenocopy Split hand/ split foot malformation. www.indiandentalacademy.com0
Msx-Dlx interaction The Msx expression is restricted to cells that are proliferating or dying whereas Dlx expression is found in regions undergoing differentiation or are capable of doing so. Accordingly Msx and Dlx proteins appear to have opposite transcription factors- Msx proteins function as transcriptional repressos while Dlx proteins are activators. www.indiandentalacademy.com0
Role of Msx-Dlx in tooth development Msx and Dlx genes participate in tooth development by reciprocal epithelialmesenchymal interaction. As the epithelium of the prospective oral cavity thickens to form dental lamina, the expression of Msx2 localizes. Activation of Msx1, Msx2, Dlx1,Dlx2 in dental mesenchyme in response to BMP4 and FGF signals form the overlying epithelium. www.indiandentalacademy.com0
The BMP4 induction of Msx1 expression and subsequent Msx dependent activation and maintenance of BMP4 expression in dental mesenchyme are key steps in conferring the odontogenic potential to these tissues.
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The failure of tooth development to progress past the early bud stage in Msx1 -/- (mutant) mice and earlier arrest at laminar stage in the absence of both Msx1 and Msx2 emphasize the role of these genes in mediating signaling events.
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Mice lacking Dlx1 and Dlx2 show no defects on tooth development but Dlx1 -/-; Dlx2 -/- compound mutant mice lacking molars indicate sensitivity to Dlx1 and Dlx2 protein 2 levels in limited subset of teeth. In humans, a point mutation in Msx1 homeobox result in agenesis of second premolars and third molars in affected individuals. www.indiandentalacademy.com0
Goosecoid (Gsc) This homeobox containing gene or transcription factor, encode a paired like homeoprotein and is expressed during gastrulation in regions of the embryo with axial patterning activity. At late stages of embryogenesis, Gsc is expressed in craniofacial regions, ventral body wall and limbs. www.indiandentalacademy.com0
Rivera-Perez (1995) showed that Gsc mutants mice died soon after birth with multiple craniofacial defects and rib cage malformations. Mutant mice have been shown to exhibit a hypoplastic mandible with lack of coronoid and angular process along with several defects of other bones like maxilla, palatine bones and pterygoid plates. www.indiandentalacademy.com0
Otx gene (Otx1 and Otx2) From experiments in mice it is clear that prior to gastrulation Otx2 is expressed in epiblast and visceral endoderm and its expression becomes restricted to anterior parts of all three germ layers, as the primitive streak is formed.
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According to Matsuo et al (1995), Otx homozygous mutants fail to develop structures anterior to rhombomere 3. the Otx2 in cranial neural crest cells was evidenced by otocephaly due to defect in these cells of Otx2 homozygous mutants.
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The Bar Class The Bar class of homeobox genes consisting of Barx1 and Barx2, contains protein meant for protein-protein interaction to regulate the function of homeodomain. Both bar class genes are expressed during development of central nervous system and peripheral nervous system. They are expressed in telencephalon, diencehalon, mesencephalon, hind brain and spinal cord and in cranial and dorsal root ganglia. www.indiandentalacademy.com0
Expression of Barx 2 is most prominent in mantle layer, in which post mitotic neurons are located, the palatal floor and dorsal root ganglia, mutations of which can produce clefts of secondary palate.
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The Paired related gene (Prx and SHOT) Prx1 and Prx2 are closely related members of Prx family of homeobox genes. Prx1 in combination with Prx2 is essential to stabilize and maintain cell fates in craniofacial mesenchyme.
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Mutation experiments in mice elicited the role of Prx1 in dental mesenchyme of all tooth germs and are considered important in tooth development. Ten Berge et al found defects in external, middle and inner ear, reduction or loss of skull bones, a reduced or sometimes cleft of the mandible and limb abnormalities in Prx1/Prx2 double mutants www.indiandentalacademy.com0
Another paired related homeobox geneSHOT- with two different isomers SHOTa and SHOTb are considered homologous to human SHOX and mouse OG-12. the transcription factors encoded by this gene are expressed in the developing aorta, female genitalia, diencephalons, nasal capsule, palate, eyelid and limb. www.indiandentalacademy.com0
SHOT was mapped to human chromosome 3q25-q26. this chromosomal region is involved in development of Cornelia-de- Hange syndrome, characterized by mental retardation, microcephaly, cleft palate, abnormally situated eyelids, nose and ear deformities, as well as heart and lung defects. www.indiandentalacademy.com0
The short stature homeobox gene SHOX is associated with idiopathic short stature in humans, as seen in Turner syndrome and Leri-Weill dyschondrosteosis, while little is known about its close relative SHOX2.
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There is restricted expression of Shox2 in the anterior domain of the secondary palate in mice and humans. Shox2-/mice develop an incomplete cleft that is confined to the anterior region of the palate, an extremely rare type of clefting in humans. The Shox2-/- palatal shelves initiate, grow and elevate normally, but the anterior region fails to contact and fuse at the midline, owing to altered cell proliferation and apoptosis, leading to incomplete clefting within the presumptive hard palate. www.indiandentalacademy.com0
Tissue recombination and bead implantation experiments have revealed that signals from the anterior palatal epithelium are responsible for the restricted mesenchymal Shox2 expression. BMP activity is necessary but not sufficient for the induction of palatal Shox2 expression. Studies demonstrate an intrinsic requirement for Shox2 in palatogenesis, and support the idea that palatogenesis is differentially regulated along the anteroposterior axis. Also, the fusion of the posterior palate can occur independently of fusion in the anterior palate. www.indiandentalacademy.com0
The LIM homeobox genes
The Lhx8 transcripts are expressed in neural crest derived ectomesenchyme of the first branchial arch and also in developing tooth during the postnatal period. The role of Lhx8 gene in palatal development has been shown and in homozygous mutant mice for Lhx8 gene, the formation and elevation of palatal shelves appeared to proceed normally but failed to make contact and fuse. www.indiandentalacademy.com0
The cleft palate is a common finding in mice carrying mutations of Lhx8 gene and can be considered as a potential gene for human cleft palate also.
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Conclusions The study of gene function continues to demonstrate how an understanding of the basic science behind development can lead to advances of direct relevance to the clinician. Many human syndromes and genetic abnormalities have now been attributed to defects in individual genes.
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Mutations in genes that influence any of these processes would cause craniofacial abnormalities, such as facial clefting and craniosynostosis, which are among the most frequent congenital birth defects in humans It is only by understanding the processes involved during normal development that we can begin to unravel the mechanisms that are responsible for various craniofacial malformations. www.indiandentalacademy.com0
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Zhang Z, Song Y, Zhao X, Zhang X, FerminC, Chen Y Rescue of cleft palate in Msx1deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development. 2002 Sep;129(17):4135-46. Martyn T. Cobourne, Construction for the Modern Head: current concepts in craniofacial development J Orthod. 2000 Dec;27(4):307-14. Ang, S-L., Ou, J., Rhinn, R., Daigle, N., Stevenson, L. and Rossant, J. A targeted mouse Otx-2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain, Development, 1996 Vol.122, 243–252 www.indiandentalacademy.com0
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MacKenzie, A., Ferguson, M. W. J. and Sharpe, P. T. (1992) . Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape, Development, 115, 403–420 Satokata, I. and Maas, R. Msx-1 deficient mice exhibit cleft palate and abnormalities of craniofacial development, Nature Genetics, 1994 Vol.6, 348–355 Sharpe, P. T Homeobox genes and orofacial development, Connective Tissue Research, 1995 Vol.32, 17–25 www.indiandentalacademy.com0
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