Molecular basis part 1/certified fixed orthodontic courses by Indian dental academy

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  • Stem cells are primal cells found in all multi-cellular organisms that retain the ability to renew themselves through mitotic cell division and can differentiate into a diverse range of specialized cell types. The three broad categories of mammalian stem cells are: embryonic stem cells, derived from blastocysts, adult stem cells, which are found in adult tissues, and cord blood stem cells, which are found in the umbilical cord. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells.
  • Cord blood is collected after the umbilical cord has been detached from the newborn, and utilized as a source of stem cells for transplantation.
  • The frontonasal prominence contributes to the forehead, the middle of the nose, the philtrum of the upper lip and the primary palate, while the lateral nasal prominence forms the sides (ala) of the nose (Larson, 2001 ) (Fig. 1). Until recently, it was thought that the ventral region of the first pharyngeal (branchial) arch gave rise to the mandibular prominence and therefore the lower jaw, and that the dorsal region of the first arch gave rise to the maxillary prominences, which form the sides of the middle and lower face, the lateral borders of the lips, and the secondary palate (Fig. 1).
  • Fig. 1. Development of the craniofacial primordia. (A-D) A frontal view of the prominences that give rise to the main structures of the face. The frontonasal (or median nasal) prominence (red) contributes to the forehead (A), the middle of the nose (B), the philtrum of the upper lip (C) and the primary palate (D), while the lateral nasal prominence (blue) forms the sides of the nose (B,D). The maxillomandibular prominences (green) give rise to the lower jaw (specifically from the mandibular prominences), to the sides of the middle and lower face, to the lateral borders of the lips, and to the secondary palate (from the maxillary prominences).
  • Any of several salamanders (genus Ambystoma) native to Mexico and the western United States that, unlike most amphibians, often retain their external gills and become sexually mature without undergoing metamorphosis.
  • The molecular mechanisms underlying the generation of segmental pattern are now beginning to be unravelled. To date most of our work has focused upon how segmental patterns of gene expression are translated into morphologically segmented cell groups.
  • Neurulation begins with a unified layer of ectoderm, underneath which lies the endoderm. A single ectomere is shown in yellow. Ectomeres are discrete regions of superficial ectoderm that exhibit a segmented pattern of gene expression. Fate-mapping experiments suggest that, together with neural crest and neuroectoderm, they define a larger developmental unit (Couly and Le Douarin, 1999). Later, these tissues act on signaling centers in the facial prominences (Hu et al., 2003 ).
    (B) The ectoderm begins to fold upwards, giving rise to the neural folds. During this process, interactions between signaling molecules begin to delineate the medial ectoderm as being neural (green) and the lateral regions of ectoderm as being non-neural (blue). The prechordal plate mesendoderm (pcp) and the buccopharyngeal membrane (bpm) become evident at this stage.
  • (C) The neural tube forms upon fusion of the neural folds, giving rise to discrete neuroectoderm (green) and surface ectoderm (blue). Around the same time, the border region between the neuroectoderm and surface ectoderm gives rise to neural crest cells. The surface ectoderm and neuroectoderm of single ectomeres remain aligned during this process.
  • (D) Neurulation completes upon formation of the neural tube, and neural crest cells (nc) lie sandwiched between the facial (surface) ectoderm and the neuroectoderm. Again, the individual neuroectoderm and surface ectoderm components of the ectomere remain in register.
  • A genetic screen (often shortened to screen) is a procedure or test to identify and select individuals who possess a phenotype of interest A basic screen involves looking for a phenotype of interest in the mutated population. One might screen for obvious phenotypes such as fruit flies with no wings or an Arabidopsis flower with no petals..
  • In evolutionary biology, homology is any similarity between characters that is due to their shared ancestry. There are examples in different branches of biology. Anatomical structures that perform the same function in different biological species and evolved from the same structure in some ancestor species are homologous. In genetics, homology is measured by comparing protein or DNA sequences, and genes that share a high sequence identity or similarity support the hypothesis that they share a common ancestor and are therefore homologous.
  • Translation is the second process of protein biosynthesis (part of the overall process of gene expression). Translation occurs in the cytoplasm where the ribosomes are located. Ribosomes are made of a small and large subunit which surrounds the mRNA. In translation, messenger RNA (mRNA) is decoded to produce a specific polypeptide according to the rules specified by the genetic code. This is the process that converts an mRNA sequence into a chain of amino acids that form a protein. Translation is necessarily preceded by transcription. Transcription proceeds in four phases: activation, initiation, elongation and termination (all describing the growth of the amino acid chain, or polypeptide that is the product of translation).
  • An intein is a segment of a protein that is able to excise itself and rejoin the remaining portions (the exteins) with a peptide bond. Inteins have also been called "protein introns".
  • In chemistry, a ligand is an atom, ion, or molecule (see also: functional group) that generally donates one or more of its electrons through a coordinate covalent bond to, or shares its electrons through a covalent bond with, one or more central atoms or ions (these ligands act as a Lewis base). But in organic chemistry ligands are also used to protect functional groups, or to stabilize reactive compounds. The molecule resulting from the coordination of a ligand (or an array of ligands) to a central atom is termed a complex.
  • glioma-associated oncogene
    Smoothened is a 7TM protein of the hedgehog pathway conserved from flies to humans. It is the molecular target of the teratogen cyclopamine.[1]
  • A protein-coding gene is transcribed into a pre-mRNA. Pre-mRNA is processed into a mature mRNA. mRNA exits the nucleus. mRNA is translated on ribosomes to produce the polypeptide chain.
  • Messenger Ribonucleic Acid (mRNA) is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein. In mRNA as in DNA, genetic information is encoded in the sequence of four nucleotides arranged into codons of three bases each. Each codon encodes for a specific amino acid, except the stop codons that terminate protein synthesis. This process requires two other types of RNA: Transfer RNA (tRNA) mediates recognition of the codon and provides the corresponding amino acid, while Ribosomal RNA (rRNA) is the central component of the ribosome's protein manufacturing machinery.
  • Molecular basis part 1/certified fixed orthodontic courses by Indian dental academy

    1. 1. Molecular Basis ofMolecular Basis of Craniofacial GrowthCraniofacial Growth INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.comwww.indiandentalacademy.com
    2. 2. DEVELOPMENTAL BIOLOGYDEVELOPMENTAL BIOLOGY GROWTH DIFFERENTIATIONMORPHOGENESIS Developmental biology is the study of the process by which organisms grow and develop. www.indiandentalacademy.comwww.indiandentalacademy.com
    3. 3. GROWTHGROWTH It is the physiochemical process by which anIt is the physiochemical process by which an organism becomes larger.organism becomes larger. [Salzmann][Salzmann] Growth usually refers to an increase in size orGrowth usually refers to an increase in size or number. It is largely an anatomic phenomenon.number. It is largely an anatomic phenomenon. [Proffit][Proffit] www.indiandentalacademy.comwww.indiandentalacademy.com
    4. 4. A normal process of increase in size of anA normal process of increase in size of an organism as a result of accretion of tissueorganism as a result of accretion of tissue similar to that originally present.similar to that originally present. www.indiandentalacademy.comwww.indiandentalacademy.com
    5. 5. www.indiandentalacademy.comwww.indiandentalacademy.com
    6. 6. DIFFERENTIATIONDIFFERENTIATION Cellular differentiationCellular differentiation is a concept fromis a concept from developmental biology describing thedevelopmental biology describing the process by which cells acquire a "type".process by which cells acquire a "type". The morphology of a cell may changeThe morphology of a cell may change dramatically during differentiation, but thedramatically during differentiation, but the genetic material remains the same.genetic material remains the same. www.indiandentalacademy.comwww.indiandentalacademy.com
    7. 7. www.indiandentalacademy.comwww.indiandentalacademy.com
    8. 8. A cell that is able to differentiate into manyA cell that is able to differentiate into many cell types is known ascell types is known as pluripotentpluripotent.. These cells are calledThese cells are called stem cellsstem cells inin animals.animals. A cell that is able to differentiate into all cellA cell that is able to differentiate into all cell types is known astypes is known as totipotenttotipotent.. In mammals,In mammals, only the zygote and early embryonic cellsonly the zygote and early embryonic cells areare totipotenttotipotent.. www.indiandentalacademy.comwww.indiandentalacademy.com
    9. 9. Embryonic stemEmbryonic stem cellscells are stem cellsare stem cells derived from thederived from the inner cell mass of aninner cell mass of an early stage embryoearly stage embryo known as aknown as a blastocyst.blastocyst. Human embryos reach the blastocyst stageHuman embryos reach the blastocyst stage 4-5 days post fertilization, at which time they4-5 days post fertilization, at which time they consist of 50-150 cells.consist of 50-150 cells. www.indiandentalacademy.comwww.indiandentalacademy.com
    10. 10. www.indiandentalacademy.comwww.indiandentalacademy.com
    11. 11. Adult stem cellsAdult stem cells are undifferentiated cellsare undifferentiated cells found throughout the body that divide tofound throughout the body that divide to replenish dying cells and regeneratereplenish dying cells and regenerate damaged tissues. Also known asdamaged tissues. Also known as somaticsomatic stem cells.stem cells. Umbilical cord bloodUmbilical cord blood is human blood fromis human blood from the placenta and umbilical cord that is rich inthe placenta and umbilical cord that is rich in hematopoietic stem cells.hematopoietic stem cells. www.indiandentalacademy.comwww.indiandentalacademy.com
    12. 12. MORPHOGENESISMORPHOGENESIS Derived from the GreekDerived from the Greek wordword morphêmorphê shape andshape and genesisgenesis creationcreation It is one of three fundamental aspects ofIt is one of three fundamental aspects of developmental biology along with the control ofdevelopmental biology along with the control of cell growth and cellular differentiation.cell growth and cellular differentiation. www.indiandentalacademy.comwww.indiandentalacademy.com
    13. 13. Morphogenesis is concerned with theMorphogenesis is concerned with the shapes of tissues, organs and entireshapes of tissues, organs and entire organisms and the positions of the variousorganisms and the positions of the various specialized cell types.specialized cell types. www.indiandentalacademy.comwww.indiandentalacademy.com
    14. 14. MOLECULAR BASIS OFMOLECULAR BASIS OF CRANIOFACIAL DEVELOPMENTCRANIOFACIAL DEVELOPMENT www.indiandentalacademy.comwww.indiandentalacademy.com
    15. 15. The development of theThe development of the craniofacial region is ancraniofacial region is an amalgamation of complexamalgamation of complex processes that need to beprocesses that need to be coordinated to produce acoordinated to produce a working unit such as aworking unit such as a calvarium, cranial base, orcalvarium, cranial base, or palate.palate. www.indiandentalacademy.comwww.indiandentalacademy.com
    16. 16. A common theme in the earlyA common theme in the early development of craniofacialdevelopment of craniofacial structures is balancing the level ofstructures is balancing the level of progenitor populations by growthprogenitor populations by growth factor signaling.factor signaling. This is to form a large enoughThis is to form a large enough population of progenitor cells beforepopulation of progenitor cells before differentiation, or that thedifferentiation, or that the proliferation is maintained for theproliferation is maintained for the outgrowth of the element.outgrowth of the element. www.indiandentalacademy.comwww.indiandentalacademy.com
    17. 17. What is the MolecularWhat is the Molecular basis of growthbasis of growth ? www.indiandentalacademy.comwww.indiandentalacademy.com
    18. 18. Several types of molecules are particularlySeveral types of molecules are particularly important during growth, differentiation andimportant during growth, differentiation and morphogenesis.morphogenesis. MorphogensMorphogens are soluble molecules that canare soluble molecules that can diffuse and carry signals that control celldiffuse and carry signals that control cell differentiation decisions in adifferentiation decisions in a concentration-concentration- dependent fashion.dependent fashion. www.indiandentalacademy.comwww.indiandentalacademy.com
    19. 19. MORPHOGENSMORPHOGENS typically acttypically act through binding to specificthrough binding to specific protein receptors. Anprotein receptors. An important class of moleculesimportant class of molecules involved in morphogenesisinvolved in morphogenesis are transcription factorare transcription factor proteins that determine theproteins that determine the fate of cells by interacting withfate of cells by interacting with DNA.DNA. www.indiandentalacademy.comwww.indiandentalacademy.com
    20. 20. These can be coded for byThese can be coded for by master regulatorymaster regulatory genesgenes and either activate or deactivate theand either activate or deactivate the transcription of other genes and, in turn,transcription of other genes and, in turn, these secondary gene products can regulatethese secondary gene products can regulate the expression of still other genes in athe expression of still other genes in a regulatory cascade.regulatory cascade. Another class of molecules involved inAnother class of molecules involved in morphogenesis are molecules that controlmorphogenesis are molecules that control cell adhesioncell adhesion.. www.indiandentalacademy.comwww.indiandentalacademy.com
    21. 21. For all intents and purposes, craniofacialFor all intents and purposes, craniofacial development is initiated as soon as thedevelopment is initiated as soon as the anteroposterior axis of an embryo is establishedanteroposterior axis of an embryo is established The ability to specify aThe ability to specify a head structurehead structure, rather than, rather than reiterate another body segment, was a crucial step inreiterate another body segment, was a crucial step in vertebrate evolution that corresponded to thevertebrate evolution that corresponded to the acquisition of two cell populations:acquisition of two cell populations: the neural crestthe neural crest and the ectodermal placodesand the ectodermal placodes (reviewed by Basch et al., 2004(reviewed by Basch et al., 2004 ; McCabe et al.,; McCabe et al., 20042004 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    22. 22. In recent years, new data have begun toIn recent years, new data have begun to reveal how the neural crest cell population isreveal how the neural crest cell population is actually generated, what types of controls areactually generated, what types of controls are in place to modifyin place to modify neural crest cell migrationneural crest cell migration and, ultimately, the role that this celland, ultimately, the role that this cell population plays in establishing the pattern ofpopulation plays in establishing the pattern of the craniofacial skeleton.the craniofacial skeleton. Although the neural crest receives aAlthough the neural crest receives a significant amount of attention, it is not thesignificant amount of attention, it is not the only craniofacial tissue with patterningonly craniofacial tissue with patterning information.information. www.indiandentalacademy.comwww.indiandentalacademy.com
    23. 23. This seminar today focuses on innovativeThis seminar today focuses on innovative studies that have addressed these issues,studies that have addressed these issues, sometimes with new and unexpectedsometimes with new and unexpected results.results. www.indiandentalacademy.comwww.indiandentalacademy.com
    24. 24. In the beginningIn the beginning …… www.indiandentalacademy.comwww.indiandentalacademy.com
    25. 25. Although the postnatalAlthough the postnatal vertebrate head exhibitsvertebrate head exhibits an exceedingly intricatean exceedingly intricate and varied morphology,and varied morphology, the craniofacial complexthe craniofacial complex initially has a much moreinitially has a much more simple geometry.simple geometry. It consisting of a series of swellings or that undergoIt consisting of a series of swellings or that undergo growth, fusion and expansion.growth, fusion and expansion. www.indiandentalacademy.comwww.indiandentalacademy.com
    26. 26. There are seven prominences that comprise theThere are seven prominences that comprise the vertebrate face.vertebrate face.www.indiandentalacademy.comwww.indiandentalacademy.com
    27. 27. Until recently, it was thought that the ventralUntil recently, it was thought that the ventral region of the first pharyngeal (branchial) archregion of the first pharyngeal (branchial) arch gave rise to the mandibular prominence andgave rise to the mandibular prominence and therefore the lower jaw.therefore the lower jaw. It was also believed that the dorsal region ofIt was also believed that the dorsal region of the first arch gave rise to the maxillarythe first arch gave rise to the maxillary prominences, which form the sides of theprominences, which form the sides of the middle and lower face, the lateral borders ofmiddle and lower face, the lateral borders of the lips, and the secondary palate.the lips, and the secondary palate. www.indiandentalacademy.comwww.indiandentalacademy.com
    28. 28. Two new studies, carried out in avians andTwo new studies, carried out in avians and axolotls, contest this view and demonstrateaxolotls, contest this view and demonstrate that at least part of this is incorrect.that at least part of this is incorrect. Both groups show that the ventral region ofBoth groups show that the ventral region of the first arch actually gives rise to boththe first arch actually gives rise to both maxillary and mandibular skeletal elements,maxillary and mandibular skeletal elements, rather than to only the mandibular elements,rather than to only the mandibular elements, as previously thought.as previously thought. (Cerny et al., 2004(Cerny et al., 2004 ; Lee et al., 2004; Lee et al., 2004 )) www.indiandentalacademy.comwww.indiandentalacademy.com
    29. 29. When considering the origami-like process ofWhen considering the origami-like process of tissue folding, flexure and growth that ultimatelytissue folding, flexure and growth that ultimately results in a face, one must also bear in mind thatresults in a face, one must also bear in mind that the cells comprising the face have undergone athe cells comprising the face have undergone a massive relocation.massive relocation. This relocation occurs owing to both activeThis relocation occurs owing to both active neuralneural crest cell migrationcrest cell migration and the passive displacementand the passive displacement of tissue that is associated withof tissue that is associated with neurulationneurulation andand headhead flexureflexure.. www.indiandentalacademy.comwww.indiandentalacademy.com
    30. 30. NEURULATIONNEURULATION www.indiandentalacademy.comwww.indiandentalacademy.com
    31. 31. It is the process of development of theIt is the process of development of the NEURAL PLATENEURAL PLATE – results from the– results from the thickening of the ectoderm overlying thethickening of the ectoderm overlying the Notochord.Notochord. NEUROECTODERMNEUROECTODERM – cells comprising the– cells comprising the neural plate.neural plate. Folding to produceFolding to produce NEURAL TUBENEURAL TUBE – lateral– lateral edges of the neural plate get elevated to formedges of the neural plate get elevated to form the neural foldsthe neural foldswww.indiandentalacademy.comwww.indiandentalacademy.com
    32. 32. www.indiandentalacademy.comwww.indiandentalacademy.com
    33. 33. Neurulation begins with a unified layer ofNeurulation begins with a unified layer of ectoderm, underneath which lies theectoderm, underneath which lies the endoderm.endoderm. www.indiandentalacademy.comwww.indiandentalacademy.com
    34. 34. • EctomeresEctomeres are discrete regions of superficialare discrete regions of superficial ectoderm that exhibit a segmented pattern ofectoderm that exhibit a segmented pattern of gene expression.gene expression. • Together with neural crest and neuroTogether with neural crest and neuro ectoderm, they define a largerectoderm, they define a larger developmental unit .developmental unit . (Couly and Le Douarin, 1999).(Couly and Le Douarin, 1999). • Later, these tissues act on signaling centersLater, these tissues act on signaling centers in thein the facial prominencesfacial prominences (Hu et al., 2003(Hu et al., 2003 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    35. 35. The ectoderm begins to fold upwards, giving rise toThe ectoderm begins to fold upwards, giving rise to the neural folds. During this process, interactionsthe neural folds. During this process, interactions between signaling molecules begin to delineate thebetween signaling molecules begin to delineate the medial ectoderm as being neural (green) and themedial ectoderm as being neural (green) and the lateral regions of ectoderm as being non-neural (blue).lateral regions of ectoderm as being non-neural (blue). www.indiandentalacademy.comwww.indiandentalacademy.com
    36. 36. The neural tube forms upon fusion of the neural folds,The neural tube forms upon fusion of the neural folds, giving rise to discrete neuroectoderm (green) andgiving rise to discrete neuroectoderm (green) and surface ectoderm (blue). Around the same time, thesurface ectoderm (blue). Around the same time, the border region between the neuroectoderm and surfaceborder region between the neuroectoderm and surface ectoderm gives rise to neural crest cellsectoderm gives rise to neural crest cells..www.indiandentalacademy.comwww.indiandentalacademy.com
    37. 37. Neurulation completes upon formation of the neuralNeurulation completes upon formation of the neural tube, and neural crest cells (nc) lie sandwichedtube, and neural crest cells (nc) lie sandwiched between the facial (surface) ectoderm and thebetween the facial (surface) ectoderm and the neuroectoderm.neuroectoderm. www.indiandentalacademy.comwww.indiandentalacademy.com
    38. 38. Sagittal section through neural tube of aSagittal section through neural tube of a chick embryo, showing neural crest (nc)chick embryo, showing neural crest (nc) located between surface ectoderm (se) andlocated between surface ectoderm (se) and neuroectoderm (ne). L, lateral; M, medial.neuroectoderm (ne). L, lateral; M, medial. www.indiandentalacademy.comwww.indiandentalacademy.com
    39. 39. The neural tube is the primodium of the C.N.S . TheThe neural tube is the primodium of the C.N.S . The anterior region forms the Fore brain, Hind brainanterior region forms the Fore brain, Hind brain AND Mid brain. Eight bulges form in the hind brainAND Mid brain. Eight bulges form in the hind brain known asknown as RHOMBOMERESRHOMBOMERES.. Neural crest cell which arise from the neural foldsNeural crest cell which arise from the neural folds migrate through out the body to form variedmigrate through out the body to form varied structures. They migrate from each rhombomere tostructures. They migrate from each rhombomere to a specified location.a specified location. Neural crest cells needed for development of faceNeural crest cells needed for development of face and first pharyngeal arch structures arise from –and first pharyngeal arch structures arise from – MID BRAIN and RHOMBOMERES 1,2 & 3.MID BRAIN and RHOMBOMERES 1,2 & 3. www.indiandentalacademy.comwww.indiandentalacademy.com
    40. 40. NEURAL CREST MIGRATIONNEURAL CREST MIGRATION ANDAND ECTODERM ALIGNMENTECTODERM ALIGNMENT www.indiandentalacademy.comwww.indiandentalacademy.com
    41. 41. As the closed neural tube begins to differentiateAs the closed neural tube begins to differentiate into the central nervous system, the neuralinto the central nervous system, the neural crest begins to migrate anteriorly from specificcrest begins to migrate anteriorly from specific rhombomeres (r1-r3) into discrete regions ofrhombomeres (r1-r3) into discrete regions of the face.the face. www.indiandentalacademy.comwww.indiandentalacademy.com
    42. 42. During this process, the neuroectoderm (ne)During this process, the neuroectoderm (ne) and surface ectoderm (se) components of theand surface ectoderm (se) components of the ectomeres continue to remain aligned (yellowectomeres continue to remain aligned (yellow arrows in C).arrows in C). www.indiandentalacademy.comwww.indiandentalacademy.com
    43. 43. As neural crest migration nears completion, theAs neural crest migration nears completion, the neuroectoderm and facial ectoderm are noneuroectoderm and facial ectoderm are no longer aligned.longer aligned. www.indiandentalacademy.comwww.indiandentalacademy.com
    44. 44. CREATING THECREATING THE NEUROECTODERM-SURFACENEUROECTODERM-SURFACE ECTODERM BOUNDARYECTODERM BOUNDARY www.indiandentalacademy.comwww.indiandentalacademy.com
    45. 45. One of the first crucial steps in craniofacialOne of the first crucial steps in craniofacial development occurs when head ectodermdevelopment occurs when head ectoderm is subdivided into non-neural and neuralis subdivided into non-neural and neural regionsregions This effectively establishes which headThis effectively establishes which head epithelium will lie outside of the cranialepithelium will lie outside of the cranial neural crest and which will lie inside it.neural crest and which will lie inside it. www.indiandentalacademy.comwww.indiandentalacademy.com
    46. 46. A subset of epithelial cells located at thisA subset of epithelial cells located at this neural/non-neural boundary separate fromneural/non-neural boundary separate from the epithelium, adopt a mesenchymalthe epithelium, adopt a mesenchymal character and come between these twocharacter and come between these two epithelia as they start their migration.epithelia as they start their migration. www.indiandentalacademy.comwww.indiandentalacademy.com
    47. 47. The epithelial-mesenchymal transition thatThe epithelial-mesenchymal transition that marks the birth date of the neural crest, thismarks the birth date of the neural crest, this shift is upon bone morphogenetic proteinshift is upon bone morphogenetic protein (Bmp)(Bmp) signaling.signaling. WhenWhen BmpBmp signaling is inhibited by thesignaling is inhibited by the overexpression of noggin, a Bmp antagonist,overexpression of noggin, a Bmp antagonist, this transition is blocked and neural crest cellsthis transition is blocked and neural crest cells are no longer generated from the margins ofare no longer generated from the margins of the neural foldsthe neural folds (Burstyn-Cohen et al., 2004(Burstyn-Cohen et al., 2004 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    48. 48. NogginNoggin is a polypeptide that binds to membersis a polypeptide that binds to members of the TGF-β superfamily of proteins. It is a Boneof the TGF-β superfamily of proteins. It is a Bone morphogenetic protein inhibitor.morphogenetic protein inhibitor.www.indiandentalacademy.comwww.indiandentalacademy.com
    49. 49. Bmp signaling achieves this effect in part byBmp signaling achieves this effect in part by regulatingregulating Wnt1Wnt1 genegene In turn,In turn, WntWnt signaling appears to be essentialsignaling appears to be essential for the generation of neural crest cells asfor the generation of neural crest cells as inhibition of its activity can block theinhibition of its activity can block the production of neural crest cells (Garcia-Castroproduction of neural crest cells (Garcia-Castro et al 2005)et al 2005) www.indiandentalacademy.comwww.indiandentalacademy.com
    50. 50. In addition toIn addition to BmpBmp andand WntWnt proteins, severalproteins, several new molecules have also been implicated innew molecules have also been implicated in the generation or early migration of neuralthe generation or early migration of neural crest cells.crest cells. Sox transcription factorsSox transcription factors, which are well, which are well known for their roles in skeletogenic cell fateknown for their roles in skeletogenic cell fate and sex determination, are also involved inand sex determination, are also involved in generating neural crest cellsgenerating neural crest cells (Cheung and(Cheung and Briscoe, 2003 ; Perez-Alcala et al., 2004Briscoe, 2003 ; Perez-Alcala et al., 2004 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    51. 51. These studies indicate that the overexpressionThese studies indicate that the overexpression ofof Sox genesSox genes lengthens the developmentallengthens the developmental window during which cranial and trunk neuralwindow during which cranial and trunk neural crest cells can be induced, and then promotescrest cells can be induced, and then promotes neural crest-like characteristics in those cells.neural crest-like characteristics in those cells. www.indiandentalacademy.comwww.indiandentalacademy.com
    52. 52. Neural crest contributions toNeural crest contributions to craniofacial patterningcraniofacial patterning www.indiandentalacademy.comwww.indiandentalacademy.com
    53. 53. Which tissue controls facial patterning?Which tissue controls facial patterning? The answer to this question continues to beThe answer to this question continues to be debated. In two recent studies, the contributiondebated. In two recent studies, the contribution of the neural crest to facial patterning wasof the neural crest to facial patterning was assessed byassessed by swapping neural crest cellsswapping neural crest cells between ducks and quails.between ducks and quails. www.indiandentalacademy.comwww.indiandentalacademy.com
    54. 54. It was found that switchingIt was found that switching frontonasalfrontonasal neural crestneural crest cells between ducks andcells between ducks and quails resulted in alterations to such anquails resulted in alterations to such an extent that ducks with quail frontonasalextent that ducks with quail frontonasal neural crest cells had a quail-like beak,neural crest cells had a quail-like beak, and quails carrying duck neural crest cellsand quails carrying duck neural crest cells had a duck-like beak.had a duck-like beak. (Schneider and Helms, 2003(Schneider and Helms, 2003 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    55. 55. Tucker and Lumsden reached a near-Tucker and Lumsden reached a near- identical conclusion when they independentlyidentical conclusion when they independently performed the same types of inter-speciesperformed the same types of inter-species transplants.transplants. They, too, found that the capacity to formThey, too, found that the capacity to form species-specific skeletal elements in thespecies-specific skeletal elements in the head is an inherent property of thehead is an inherent property of the neuralneural crest cells.crest cells. (Tucker and Lumsden, 2004(Tucker and Lumsden, 2004 )) www.indiandentalacademy.comwww.indiandentalacademy.com
    56. 56. It should be emphasized that in both theseIt should be emphasized that in both these studies,studies, the extent to which facial featuresthe extent to which facial features were transformed was directly proportionalwere transformed was directly proportional to the number of transplanted neural crestto the number of transplanted neural crest cells.cells. In other words, the transformation was aIn other words, the transformation was a ``population-dependentpopulation-dependent' effect, as was' effect, as was reported in much earlier transplantationreported in much earlier transplantation studiesstudies (Andres, 1949(Andres, 1949 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    57. 57. So it seems that only when theSo it seems that only when the contingencycontingency isis largelarge enough do neural crest cells followenough do neural crest cells follow molecular cues that are generated andmolecular cues that are generated and maintained by the assemblage itself,maintained by the assemblage itself, disregarding signals emanating from thedisregarding signals emanating from the local environment.local environment. When the numbers ofWhen the numbers of transplanted cellstransplanted cells areare below some crucial threshold, then theybelow some crucial threshold, then they appear to respond to local cues from theappear to respond to local cues from the surrounding epithelia.surrounding epithelia. www.indiandentalacademy.comwww.indiandentalacademy.com
    58. 58. Just what these population-dependent cuesJust what these population-dependent cues are, and how many cells are required toare, and how many cells are required to maintain them, ismaintain them, is unknown.unknown. What we do know, however, is that facialWhat we do know, however, is that facial morphogenesis is the cumulative result ofmorphogenesis is the cumulative result of reciprocal signaling between and among all ofreciprocal signaling between and among all of these tissues, and that the debatable issue ofthese tissues, and that the debatable issue of which tissue contains patterningwhich tissue contains patterning information becomes a question of timinginformation becomes a question of timing.. www.indiandentalacademy.comwww.indiandentalacademy.com
    59. 59. Preview of next seminar:Preview of next seminar: Epithelial contribution to craniofacial patterningEpithelial contribution to craniofacial patterning Oral ectoderm and tooth patterningOral ectoderm and tooth patterning Pharyngeal endoderm and arch patterningPharyngeal endoderm and arch patterning Neural and surface ectoderm: patterning the middleNeural and surface ectoderm: patterning the middle and upper faceand upper face Molecular mediators of craniofacial morphogenesisMolecular mediators of craniofacial morphogenesis A sonic boomA sonic boom HOX genesHOX genes Fgfs and craniofacial patterning: a question ofFgfs and craniofacial patterning: a question of timingtiming Bmp proteins and craniofacial patterningBmp proteins and craniofacial patterning Bmp4 and craniofacial patterningBmp4 and craniofacial patterning Patterning of the jawPatterning of the jaw www.indiandentalacademy.comwww.indiandentalacademy.com
    60. 60. THANK YOU . . .THANK YOU . . . www.indiandentalacademy.comwww.indiandentalacademy.com
    61. 61. Molecular Basis ofMolecular Basis of Craniofacial GrowthCraniofacial Growth Presented by :Presented by : Dr. MahimaDr. Mahima NandaNandawww.indiandentalacademy.comwww.indiandentalacademy.com
    62. 62. No region of our anatomy more powerfullyNo region of our anatomy more powerfully conveys our emotions nor elicits moreconveys our emotions nor elicits more profound reactions when disease orprofound reactions when disease or genetic disorders disfigure it than the face.genetic disorders disfigure it than the face. www.indiandentalacademy.comwww.indiandentalacademy.com
    63. 63. Recent progress has beenRecent progress has been made towards defining themade towards defining the tissue interactions andtissue interactions and molecular mechanisms thatmolecular mechanisms that control craniofacialcontrol craniofacial morphogenesis.morphogenesis. www.indiandentalacademy.comwww.indiandentalacademy.com
    64. 64. Some insights have comeSome insights have come from genetic manipulationsfrom genetic manipulations and others from tissueand others from tissue recombination andrecombination and biochemical approaches,biochemical approaches, which have revealed thewhich have revealed the molecular underpinningsmolecular underpinnings of morphogenesis.of morphogenesis. www.indiandentalacademy.comwww.indiandentalacademy.com
    65. 65. Changes in craniofacial architecture alsoChanges in craniofacial architecture also lie at the heart of evolutionary adaptation,lie at the heart of evolutionary adaptation, as new studies in attest.as new studies in attest. Together, these findings reveal muchTogether, these findings reveal much about molecular and tissue interactionsabout molecular and tissue interactions behind craniofacial development.behind craniofacial development. www.indiandentalacademy.comwww.indiandentalacademy.com
    66. 66. Sometimes, the mechanisms that regulateSometimes, the mechanisms that regulate normal development are best appreciatednormal development are best appreciated by studying cases of abnormalby studying cases of abnormal development.development. Human craniofacial malformations haveHuman craniofacial malformations have been avidly catalogued since thebeen avidly catalogued since the Aristotelian era but only lately haveAristotelian era but only lately have researchers pinpointed some of the genesresearchers pinpointed some of the genes responsible.responsible. www.indiandentalacademy.comwww.indiandentalacademy.com
    67. 67. The next hurdle is to understand the function ofThe next hurdle is to understand the function of the encoded proteins in craniofacialthe encoded proteins in craniofacial morphogenesis.morphogenesis. This aim is complicated by the fact that theseThis aim is complicated by the fact that these genes are invariably expressed in multiplegenes are invariably expressed in multiple tissues and at multiple times during facialtissues and at multiple times during facial development, and so separating their numerousdevelopment, and so separating their numerous functions becomes a difficult task.functions becomes a difficult task. www.indiandentalacademy.comwww.indiandentalacademy.com
    68. 68. The importance of genes on developmentThe importance of genes on development has been know for a long time.has been know for a long time. In Drosophila a class ofIn Drosophila a class of Master regulatoryMaster regulatory genesgenes were know to exist long beforewere know to exist long before molecular basis was known.molecular basis was known. Genes known to control segmentGenes known to control segment differentiation were calleddifferentiation were called HomeoticHomeotic GenesGenes.. www.indiandentalacademy.comwww.indiandentalacademy.com
    69. 69. Mutations of these genes caused parts toMutations of these genes caused parts to develop in inappropriate places.develop in inappropriate places. This process of transformation was calledThis process of transformation was called HOMEOSISHOMEOSIS by Bateson back in theby Bateson back in the 1940s.1940s. www.indiandentalacademy.comwww.indiandentalacademy.com
    70. 70. Here, a mutation of theHere, a mutation of the AntennapediaAntennapedia genegene causes a leg to develop in place of thecauses a leg to develop in place of the antenna. Note the littleantenna. Note the little HaltereHaltere (balancer) on(balancer) on the segment behind the wing.the segment behind the wing. www.indiandentalacademy.comwww.indiandentalacademy.com
    71. 71. The next slide shows homeotic mutationThe next slide shows homeotic mutation that results in transformation of this halterethat results in transformation of this haltere into a second wing.into a second wing. www.indiandentalacademy.comwww.indiandentalacademy.com
    72. 72. Molecular mediators ofMolecular mediators of craniofacial morphogenesiscraniofacial morphogenesis Development 132, 851-861Development 132, 851-861 (2005)(2005) Helms JA, Cordero D, TapadiaHelms JA, Cordero D, Tapadia www.indiandentalacademy.comwww.indiandentalacademy.com
    73. 73. A sonic boomA sonic boom HOX genesHOX genes Fgfs and craniofacial patterning: aFgfs and craniofacial patterning: a question of timingquestion of timing Bmp proteins and craniofacialBmp proteins and craniofacial patterningpatterning Bmp4 and craniofacial patterningBmp4 and craniofacial patterning www.indiandentalacademy.comwww.indiandentalacademy.com
    74. 74. A SONIC BOOMA SONIC BOOM !!!!!!!! www.indiandentalacademy.comwww.indiandentalacademy.com
    75. 75. The hedgehog geneThe hedgehog gene ((hhhh)) was first identifiedwas first identified in the classic Heidelberg screens of Ericin the classic Heidelberg screens of Eric Wiechaus and Christiane Nusslein-Volhard,Wiechaus and Christiane Nusslein-Volhard, as published in 1978.as published in 1978. These screens identified genes that controlThese screens identified genes that control the segmentation pattern ofthe segmentation pattern of DrosophilaDrosophila melanogastermelanogaster (fruit fly) embryos.(fruit fly) embryos. www.indiandentalacademy.comwww.indiandentalacademy.com
    76. 76. TheThe hhhh loss of functionloss of function mutant phenotypemutant phenotype causes the embryos tocauses the embryos to be covered withbe covered with denticles (small pointydenticles (small pointy projections), much likeprojections), much like a hedgehog.a hedgehog. www.indiandentalacademy.comwww.indiandentalacademy.com
    77. 77. Investigations aimed at finding aInvestigations aimed at finding a hedgehoghedgehog equivalent in mammals revealed threeequivalent in mammals revealed three homologous genes.homologous genes. The first two discovered,The first two discovered, desert hedgehogdesert hedgehog andand Indian hedgehogIndian hedgehog, were named for species of, were named for species of hedgehogs.hedgehogs. www.indiandentalacademy.comwww.indiandentalacademy.com
    78. 78. Sonic hedgehogSonic hedgehog was named afterwas named after Sega's video gameSega's video game character Sonic thecharacter Sonic the Hedgehog.Hedgehog. www.indiandentalacademy.comwww.indiandentalacademy.com
    79. 79. PROCESSINGPROCESSING SHH undergoes a series of processingSHH undergoes a series of processing steps before it is secreted from the cell.steps before it is secreted from the cell. Newly synthesised SHH is referred to asNewly synthesised SHH is referred to as thethe PREPROPROTEINPREPROPROTEIN..www.indiandentalacademy.comwww.indiandentalacademy.com
    80. 80. As a secreted protein it contains aAs a secreted protein it contains a shortshort signalsignal sequencesequence at its N-terminus, which isat its N-terminus, which is recognised by therecognised by the signal recognition particlesignal recognition particle during the translocation into theduring the translocation into the endoplasmic reticulum (ER).endoplasmic reticulum (ER). Once translocation is complete, the signalOnce translocation is complete, the signal sequence is removed by signal peptidase insequence is removed by signal peptidase in the ER.the ER. www.indiandentalacademy.comwww.indiandentalacademy.com
    81. 81. There SHH undergoes autoprocessing toThere SHH undergoes autoprocessing to generate a N-terminal signaling domaingenerate a N-terminal signaling domain (SHH-N) and a C-terminal domain with no(SHH-N) and a C-terminal domain with no known signaling role.known signaling role. The cleavage is catalysed by a proteaseThe cleavage is catalysed by a protease within the C-terminal domain. During thewithin the C-terminal domain. During the reaction, a cholesterol molecule is addedreaction, a cholesterol molecule is added to the C-terminus of SHH-N.to the C-terminus of SHH-N. www.indiandentalacademy.comwww.indiandentalacademy.com
    82. 82. Thus the C-terminal domain acts as anThus the C-terminal domain acts as an inteinintein and a cholesterol transferase.and a cholesterol transferase. Another hydrophobic moiety, a palmitate, isAnother hydrophobic moiety, a palmitate, is added to the alpha-amine of N-terminaladded to the alpha-amine of N-terminal cysteine of SHH-N.cysteine of SHH-N. This modification is required for efficientThis modification is required for efficient signaling, resulting in 30-fold increase insignaling, resulting in 30-fold increase in potency over the non-palmitylated formpotency over the non-palmitylated form www.indiandentalacademy.comwww.indiandentalacademy.com
    83. 83. www.indiandentalacademy.comwww.indiandentalacademy.com
    84. 84. HEDGEHOG SIGNALING PATHWAYHEDGEHOG SIGNALING PATHWAY..HEDGEHOG SIGNALING PATHWAYHEDGEHOG SIGNALING PATHWAY.. www.indiandentalacademy.comwww.indiandentalacademy.com
    85. 85. www.indiandentalacademy.comwww.indiandentalacademy.com
    86. 86. When SHH reaches its target cell, it binds toWhen SHH reaches its target cell, it binds to thethe Patched-1 (PTCH1)Patched-1 (PTCH1) receptor.receptor. In the absence of ligand, PTCH1 inhibitsIn the absence of ligand, PTCH1 inhibits Smoothened (SMO),Smoothened (SMO), a downstream proteina downstream protein in the pathway.in the pathway. The binding of SHH relieves SMO inhibition,The binding of SHH relieves SMO inhibition, leading to activation of the GLI transcriptionleading to activation of the GLI transcription factors: the activatorsfactors: the activators Gli1Gli1 andand Gli2Gli2 and theand the repressor[repressor[Gli3Gli3].]. www.indiandentalacademy.comwww.indiandentalacademy.com
    87. 87. ActivatedActivated GLIGLI accumulates in the nucleusaccumulates in the nucleus and controls the transcription of hedgehogand controls the transcription of hedgehog target genes.target genes. Overexpression of mutated PTCH1 playsOverexpression of mutated PTCH1 plays a role ina role in basal cell carcinomabasal cell carcinoma.. www.indiandentalacademy.comwww.indiandentalacademy.com
    88. 88. FUNCTIONFUNCTION Of theOf the hhhh homologues,homologues, shhshh has beenhas been found to have the most critical roles infound to have the most critical roles in development, acting as a morphogendevelopment, acting as a morphogen involved in patterning many systems,involved in patterning many systems, including the limb and midline structures inincluding the limb and midline structures in the brain and spinal cord.the brain and spinal cord. www.indiandentalacademy.comwww.indiandentalacademy.com
    89. 89. Members of the hedgehog family play keyMembers of the hedgehog family play key roles in a wide variety of developmentalroles in a wide variety of developmental processes.processes. One of the best studied examples is theOne of the best studied examples is the action of Sonic hedgehog duringaction of Sonic hedgehog during development of thedevelopment of the vertebrate limbvertebrate limb.. www.indiandentalacademy.comwww.indiandentalacademy.com
    90. 90. One of the best studied craniofacial abnormalitiesOne of the best studied craniofacial abnormalities isis holoprosencephaly (HPEholoprosencephaly (HPE), a syndrome that is), a syndrome that is associated with perturbations in a handful ofassociated with perturbations in a handful of ShhShh-- related genes.related genes. At one end of the HPE spectrum, fetuses exhibitAt one end of the HPE spectrum, fetuses exhibit cyclopia, a condition characterized by a single,cyclopia, a condition characterized by a single, central eye and no discernable nose, but acentral eye and no discernable nose, but a relatively normal-looking middle and lower facerelatively normal-looking middle and lower face (Chiang et al., 2001(Chiang et al., 2001 ).). At the other extreme, obligate HPE carriers canAt the other extreme, obligate HPE carriers can have a normal facial appearance (have a normal facial appearance (McKusick, 2000McKusick, 2000 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    91. 91. In an effort to explain this remarkable phenotypicIn an effort to explain this remarkable phenotypic variation, Traiffort and colleagues recentlyvariation, Traiffort and colleagues recently examined how specific human HPE mutationsexamined how specific human HPE mutations affected the structure and function of the SHHaffected the structure and function of the SHH protein.protein. The researchers found that most HPE mutationsThe researchers found that most HPE mutations fall into one of three classes:fall into one of three classes: 1.1. mutations that influencedmutations that influenced binding of the proteinbinding of the protein 2.2. those that affect thethose that affect the auto-processing of SHHauto-processing of SHH 3.3. and those thatand those that adversely alter SHH stabilityadversely alter SHH stability (Traiffort et al., 2004(Traiffort et al., 2004 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    92. 92. HoloprosencephalyHoloprosencephaly is a type of cephalic disorder.is a type of cephalic disorder. This is a disorder characterized by the failure of theThis is a disorder characterized by the failure of the prosencephalon (the forebrain of the embryo) toprosencephalon (the forebrain of the embryo) to develop.develop. During normal development the forebrain is formedDuring normal development the forebrain is formed and the face begins to develop in the fifth and sixthand the face begins to develop in the fifth and sixth weeks of human pregnancy.weeks of human pregnancy. Holoprosencephaly is caused by a failure of theHoloprosencephaly is caused by a failure of the embryo's forebrain to divide to form bilateral cerebralembryo's forebrain to divide to form bilateral cerebral hemispheres.hemispheres. www.indiandentalacademy.comwww.indiandentalacademy.com
    93. 93. Alobar holoprosencephalyAlobar holoprosencephaly - the most- the most serious form in which the brain fails toserious form in which the brain fails to separate, is usually associated with severeseparate, is usually associated with severe facial anomalies.facial anomalies. Semilobar holoprosencephalySemilobar holoprosencephaly - in which- in which the brain's hemispheres have a slightthe brain's hemispheres have a slight tendency to separate, is an intermediatetendency to separate, is an intermediate form of the disease.form of the disease. Lobar holoprosencephalyLobar holoprosencephaly - in which there- in which there is considerable evidence of separate brainis considerable evidence of separate brain hemispheres, is the least severe form.hemispheres, is the least severe form.www.indiandentalacademy.comwww.indiandentalacademy.com
    94. 94. Alobar holoprosencephalyAlobar holoprosencephaly www.indiandentalacademy.comwww.indiandentalacademy.com
    95. 95. www.indiandentalacademy.comwww.indiandentalacademy.com
    96. 96. However, none of these mutation types couldHowever, none of these mutation types could be linked to a specific phenotypebe linked to a specific phenotype (Traiffort et al., 2004(Traiffort et al., 2004 )) If there is no clear genotype-phenotypeIf there is no clear genotype-phenotype correlation, then what explains the variablecorrelation, then what explains the variable expressivity of this craniofacial malformation?expressivity of this craniofacial malformation? www.indiandentalacademy.comwww.indiandentalacademy.com
    97. 97. One appealing hypothesis is that environmentalOne appealing hypothesis is that environmental agents act in conjunction with an autosomalagents act in conjunction with an autosomal dominant mutation to compromise Shhdominant mutation to compromise Shh signaling.signaling. (Cordero et al., 2004(Cordero et al., 2004 ; Edison 2003; Edison 2003 ).). If this scenario were true, then varying the timeIf this scenario were true, then varying the time in which an embryo was exposed to anin which an embryo was exposed to an environmental teratogen could elicit differentenvironmental teratogen could elicit different disease phenotypes.disease phenotypes. www.indiandentalacademy.comwww.indiandentalacademy.com
    98. 98. Testing this hypothesis…Testing this hypothesis… Chen et al., 2002Chen et al., 2002 www.indiandentalacademy.comwww.indiandentalacademy.com
    99. 99. They exposedThey exposed avianavian embryosembryos toto cyclopaminecyclopamine,, a potenta potent inhibitorinhibitor of the Hedgehog signalingof the Hedgehog signaling pathway …..pathway ….. and found that by varying the delivery time soand found that by varying the delivery time so that it coincided withthat it coincided with ShhShh induction in theinduction in the forebrain and later in the face, we couldforebrain and later in the face, we could reproduce the spectrum of HPE phenotypes.reproduce the spectrum of HPE phenotypes. www.indiandentalacademy.comwww.indiandentalacademy.com
    100. 100. Although this is unlikely to be the sole, orAlthough this is unlikely to be the sole, or even the predominant, explanation foreven the predominant, explanation for variations in HPE phenotype, experimentsvariations in HPE phenotype, experiments such as these indicate thatsuch as these indicate that Shh has aShh has a variety of functions in facial development.variety of functions in facial development. www.indiandentalacademy.comwww.indiandentalacademy.com
    101. 101. Molecular Basis ofMolecular Basis of Craniofacial GrowthCraniofacial Growth Presented by :Presented by : Dr. MahimaDr. Mahimawww.indiandentalacademy.comwww.indiandentalacademy.com
    102. 102. Molecular mediators ofMolecular mediators of craniofacial morphogenesiscraniofacial morphogenesis continued . . .continued . . .www.indiandentalacademy.comwww.indiandentalacademy.com
    103. 103. DNADNA toto PROTIEPROTIE NN www.indiandentalacademy.comwww.indiandentalacademy.com
    104. 104. The central dogma ofThe central dogma of molecular biologymolecular biology describes the two-stepdescribes the two-step process, transcriptionprocess, transcription and translation, byand translation, by which the informationwhich the information in genes flows intoin genes flows into proteins:proteins: DNA → RNA → proteinDNA → RNA → protein www.indiandentalacademy.comwww.indiandentalacademy.com
    105. 105. The basic building block of a protein isThe basic building block of a protein is the amino acid.the amino acid. www.indiandentalacademy.comwww.indiandentalacademy.com
    106. 106. www.indiandentalacademy.comwww.indiandentalacademy.com
    107. 107. HEDGEHOG SIGNALING PATHWAYHEDGEHOG SIGNALING PATHWAY.. www.indiandentalacademy.comwww.indiandentalacademy.com
    108. 108. Fgfs and craniofacial patterningFgfs and craniofacial patterning : a question of timing: a question of timing www.indiandentalacademy.comwww.indiandentalacademy.com
    109. 109. Fibroblast growth factorsFibroblast growth factors, or, or FGFsFGFs, are a, are a family of growth factors involved in woundfamily of growth factors involved in wound healing and embryonic development.healing and embryonic development. The FGFs areThe FGFs are heparin-binding proteinsheparin-binding proteins andand interactions with cell-surface associatedinteractions with cell-surface associated heparan sulfate proteoglycans have beenheparan sulfate proteoglycans have been shown to be essential for FGF signalshown to be essential for FGF signal transductiontransduction www.indiandentalacademy.comwww.indiandentalacademy.com
    110. 110. Fibroblast growth factor was found in aFibroblast growth factor was found in a cow brain extract by Gospodarowicz andcow brain extract by Gospodarowicz and colleagues and tested in a bioassay whichcolleagues and tested in a bioassay which caused fibroblasts to proliferate (firstcaused fibroblasts to proliferate (first published report in 1974).published report in 1974). In humans, 20 members of the FGF familyIn humans, 20 members of the FGF family have been identified all of which arehave been identified all of which are structurallystructurally related signaling molecules:related signaling molecules: www.indiandentalacademy.comwww.indiandentalacademy.com
    111. 111. 1.1. MembersMembers FGF1FGF1--1010 all bind fibroblast growthall bind fibroblast growth factor receptors (FGFRs). FGF1 is alsofactor receptors (FGFRs). FGF1 is also known as "Acidic", andknown as "Acidic", and FGF2FGF2 is also knownis also known as basic FGF.as basic FGF. 2.2. MembersMembers FGF11-14FGF11-14 are involved inare involved in intracellular processes unrelated to theintracellular processes unrelated to the FGFsFGFs 3.3. MembersMembers FGF16FGF16 throughthrough FGF23FGF23 are newerare newer and not as well characterized.and not as well characterized. 4.4. FGF15 is the mouse ortholog of humanFGF15 is the mouse ortholog of human FGF19FGF19 www.indiandentalacademy.comwww.indiandentalacademy.com
    112. 112. www.indiandentalacademy.comwww.indiandentalacademy.com
    113. 113. www.indiandentalacademy.comwww.indiandentalacademy.com
    114. 114. www.indiandentalacademy.comwww.indiandentalacademy.com
    115. 115. One of the most important functions ofOne of the most important functions of bFGF (FGF2) is the promotion ofbFGF (FGF2) is the promotion of endothelial cell proliferationendothelial cell proliferation and theand the physical organization of endothelial cellsphysical organization of endothelial cells into tube-like structures.into tube-like structures. It thus promotesIt thus promotes angiogenesisangiogenesis, the growth, the growth of new blood vessels from the pre-existingof new blood vessels from the pre-existing vasculature.vasculature. www.indiandentalacademy.comwww.indiandentalacademy.com
    116. 116. bFGF is an important player inbFGF is an important player in woundwound healinghealing. It stimulates the proliferation of. It stimulates the proliferation of fibroblasts that give rise tofibroblasts that give rise to granulationgranulation tissuetissue, which fills up a wound space/cavity, which fills up a wound space/cavity early in the wound healing process.early in the wound healing process. www.indiandentalacademy.comwww.indiandentalacademy.com
    117. 117. It has also been demonstrated that fibroblastIt has also been demonstrated that fibroblast growth factors are associated with manygrowth factors are associated with many developmental processes in the craniofacialdevelopmental processes in the craniofacial region.region. This has been well illustrated in recentThis has been well illustrated in recent studies evaluating the consequences of Fgfstudies evaluating the consequences of Fgf perturbation at four separate points inperturbation at four separate points in craniofacial development.craniofacial development. www.indiandentalacademy.comwww.indiandentalacademy.com
    118. 118. Early in craniofacial development, Fgf signalingEarly in craniofacial development, Fgf signaling is crucial in establishing the midbrain-hindbrainis crucial in establishing the midbrain-hindbrain boundaryboundary (Scholpp et al., 2003)(Scholpp et al., 2003) Later in development, Fgf signaling from ventralLater in development, Fgf signaling from ventral forebrain and pharyngeal endoderm is requiredforebrain and pharyngeal endoderm is required for pharyngeal skeletogenesis, as inhibiting thisfor pharyngeal skeletogenesis, as inhibiting this pathway prevents the formation of the secondpathway prevents the formation of the second arch skeletonarch skeleton (Creuzet et al., 2004(Creuzet et al., 2004 ; Mason, 2003 ); Mason, 2003 ) www.indiandentalacademy.comwww.indiandentalacademy.com
    119. 119. Later still, blocking Fgf signaling from theLater still, blocking Fgf signaling from the surface ectoderm disrupts outgrowth of thesurface ectoderm disrupts outgrowth of the frontonasal skeletonfrontonasal skeleton (A. Abzhanov, D. Hu, J. Sen, C. J)(A. Abzhanov, D. Hu, J. Sen, C. J) Finally, just before birth, disruptions in FgfFinally, just before birth, disruptions in Fgf signaling cause premature osteogenesis insignaling cause premature osteogenesis in the sutures.the sutures. (Moore et al.; Sarkar et al.(Moore et al.; Sarkar et al. )) www.indiandentalacademy.comwww.indiandentalacademy.com
    120. 120. FGF-5FGF-5 in the embryo is notable for its highlyin the embryo is notable for its highly specific pattern of expression, first in pre-specific pattern of expression, first in pre- gastrulation embryonic ectoderm and later in agastrulation embryonic ectoderm and later in a small patch of mesoderm through which thesmall patch of mesoderm through which the hepatic bud will penetrate.hepatic bud will penetrate. Ectodermally-derivedEctodermally-derived FGF-8FGF-8 is suggested tois suggested to be important in driving the proliferation of thebe important in driving the proliferation of the underlying mesenchyme, thus adding lengthunderlying mesenchyme, thus adding length to the limb.to the limb. www.indiandentalacademy.comwww.indiandentalacademy.com
    121. 121. Clearly then, Fgfs play multiple, fundamentalClearly then, Fgfs play multiple, fundamental roles in craniofacial morphogenesis, butroles in craniofacial morphogenesis, but unraveling this complicated molecularunraveling this complicated molecular machinery will have to await better geneticmachinery will have to await better genetic and molecular tools that permit a more preciseand molecular tools that permit a more precise regulation of gene activity.regulation of gene activity. www.indiandentalacademy.comwww.indiandentalacademy.com
    122. 122. What is a homeobox?What is a homeobox? www.indiandentalacademy.comwww.indiandentalacademy.com
    123. 123. AA homeoboxhomeobox is a DNA sequence foundis a DNA sequence found within genes that are involved in thewithin genes that are involved in the regulation of development (morphogenesis)regulation of development (morphogenesis) of animals, fungi and plants.of animals, fungi and plants. Genes that have a homeobox are calledGenes that have a homeobox are called homeobox geneshomeobox genes and form theand form the homeoboxhomeobox gene familygene family.. www.indiandentalacademy.comwww.indiandentalacademy.com
    124. 124. DiscoveryDiscovery They were discovered independently inThey were discovered independently in 1983 by Walter Jakob Gehring and his1983 by Walter Jakob Gehring and his colleagues at the University of Basel,colleagues at the University of Basel, Switzerland.Switzerland. www.indiandentalacademy.comwww.indiandentalacademy.com
    125. 125. Since their discovery in 1983,Since their discovery in 1983, homeoboxhomeobox genesgenes, and the proteins they encode, the, and the proteins they encode, the homeodomain proteinshomeodomain proteins, have turned out to, have turned out to play important roles in the developmentalplay important roles in the developmental processes of many multicellular organisms.processes of many multicellular organisms. While certainly not the only developmentalWhile certainly not the only developmental control genes, they have been shown to playcontrol genes, they have been shown to play crucial roles from the earliest steps incrucial roles from the earliest steps in embryogenesisembryogenesis to the very latest steps into the very latest steps in cellcell differentiation.differentiation. www.indiandentalacademy.comwww.indiandentalacademy.com
    126. 126. HOX GENESHOX GENES Hox genes are aHox genes are a subgroupsubgroup of homeoboxof homeobox genes.genes. In vertebrates these genes are found inIn vertebrates these genes are found in gene clusters on the chromosomes.gene clusters on the chromosomes. In mammals four such clusters exist,In mammals four such clusters exist, calledcalled Hox clustersHox clusters.. www.indiandentalacademy.comwww.indiandentalacademy.com
    127. 127. The gene name "Hox" has been restrictedThe gene name "Hox" has been restricted to name Hox cluster genes in vertebrates.to name Hox cluster genes in vertebrates. Only genes in the HOX cluster should beOnly genes in the HOX cluster should be named Hox genes.named Hox genes. So note: homeobox genes are NOT HoxSo note: homeobox genes are NOT Hox genes, Hox genes are a subset ofgenes, Hox genes are a subset of homeobox genes.homeobox genes. www.indiandentalacademy.comwww.indiandentalacademy.com
    128. 128. HOX clusterHOX cluster The term Hox cluster refers to a group ofThe term Hox cluster refers to a group of clustered homeobox genes, namedclustered homeobox genes, named HoxHox genesgenes in vertebrates, that play importantin vertebrates, that play important roles in pattern formation along the anterior-roles in pattern formation along the anterior- posterior body axis.posterior body axis. www.indiandentalacademy.comwww.indiandentalacademy.com
    129. 129. HomeodomainHomeodomain:: a DNA-binding domain,a DNA-binding domain, usually about 60 amino acids in length,usually about 60 amino acids in length, encoded by the homeobox.encoded by the homeobox. HomeoboxHomeobox:: a fragment of DNA of abouta fragment of DNA of about 180 basepairs (not counting introns),180 basepairs (not counting introns), found in homeobox genes.found in homeobox genes. www.indiandentalacademy.comwww.indiandentalacademy.com
    130. 130. Here a rotating view of the homeodomainHere a rotating view of the homeodomain bound to DNAbound to DNA www.indiandentalacademy.comwww.indiandentalacademy.com
    131. 131. HUMAN GENESHUMAN GENES NAMENAME CHROMOSOMECHROMOSOME GENEGENE HOX AHOX A Chromosome 7Chromosome 7 HOXA 1-7HOXA 1-7 HOXA 9-11,HOXA 9-11, HOXA 13HOXA 13 HOX BHOX B Chromosome 17Chromosome 17 HOXB 1-9HOXB 1-9 HOX CHOX C Chromosome 12Chromosome 12 HOXC 4-6HOXC 4-6 HOXC 8-13HOXC 8-13 HOX DHOX D Chromosome 2Chromosome 2 HOXD 1HOXD 1 HOXD 3-4HOXD 3-4 HOXC 8-13HOXC 8-13www.indiandentalacademy.comwww.indiandentalacademy.com
    132. 132. If we look at the CNS earlier in embryogenesis, shortlyIf we look at the CNS earlier in embryogenesis, shortly after neurulation, and during somitogenesis,after neurulation, and during somitogenesis, segmentation is obvious in the rhombencephalon, whichsegmentation is obvious in the rhombencephalon, which is the CNS precursor of the hindbrain.is the CNS precursor of the hindbrain. In this structure and at this time there is a segmentalIn this structure and at this time there is a segmental periodicity to the expression of the most anteriorlyperiodicity to the expression of the most anteriorly expressed genes.expressed genes. So, each rhombomere has its own hox code as wellSo, each rhombomere has its own hox code as well (i.e., except R1 and R2, which do not express hox(i.e., except R1 and R2, which do not express hox genes. .genes. . Hox Gene Expression andHox Gene Expression and EmbryogenesisEmbryogenesis www.indiandentalacademy.comwww.indiandentalacademy.com
    133. 133. Key Features of this are :Key Features of this are : 1) The vertebrate homeotic complex comprises four1) The vertebrate homeotic complex comprises four distinct Hox gene clusters (Hox A, B, C, D).distinct Hox gene clusters (Hox A, B, C, D). 2) The chromosomal organization of the genes in2) The chromosomal organization of the genes in each Hox cluster reflects its anterior-posterioreach Hox cluster reflects its anterior-posterior expression in the body plan (spatial colinearity).expression in the body plan (spatial colinearity). 3) Homeotic genes are expressed within segmented3) Homeotic genes are expressed within segmented and unsegmented structures within the body plan. Hoxand unsegmented structures within the body plan. Hox gene expression in some unsegmented structuresgene expression in some unsegmented structures arise from segmented precursors.arise from segmented precursors. www.indiandentalacademy.comwww.indiandentalacademy.com
    134. 134. Bmp proteins andBmp proteins and craniofacial patterningcraniofacial patterning Initial discovery of bone morphogeneticInitial discovery of bone morphogenetic proteinprotein activityactivity was published inwas published in 19651965 by Marshall Rby Marshall R www.indiandentalacademy.comwww.indiandentalacademy.com
    135. 135. Bone Morphogenetic ProteinsBone Morphogenetic Proteins ((BMPsBMPs) are a) are a group of growth factors known for their abilitygroup of growth factors known for their ability to induce the formation ofto induce the formation of bone and cartilagebone and cartilage.. TYPESTYPES Originally, seven such proteins wereOriginally, seven such proteins were discovered, 6 of them (BMP2 through BMP7)discovered, 6 of them (BMP2 through BMP7) belong to the Transforming growth factor betabelong to the Transforming growth factor beta superfamily of proteins.superfamily of proteins. Since then, nine more BMPs have beenSince then, nine more BMPs have been discovered, bringing the total to sixteen.discovered, bringing the total to sixteen. www.indiandentalacademy.comwww.indiandentalacademy.com
    136. 136. FUNCTIONFUNCTION BMPs interact with specific receptors on the cellBMPs interact with specific receptors on the cell surface, referred to as bone morphogenetic proteinsurface, referred to as bone morphogenetic protein receptors (BMPRs).receptors (BMPRs). Signal transduction through BMPRs results inSignal transduction through BMPRs results in mobilization of members of the SMAD family ofmobilization of members of the SMAD family of proteins.proteins. The signaling pathways involving BMPs, BMPRsThe signaling pathways involving BMPs, BMPRs and SMADS are important in the development ofand SMADS are important in the development of the heart, central nervous system, and cartilage, asthe heart, central nervous system, and cartilage, as well as post-natal bone development.well as post-natal bone development. www.indiandentalacademy.comwww.indiandentalacademy.com
    137. 137. They have an important role during embryonicThey have an important role during embryonic development on the embryonic patterning anddevelopment on the embryonic patterning and early skeletal formation.early skeletal formation. As such, disruption of BMP signaling can affectAs such, disruption of BMP signaling can affect the body plan of the developing embryo. Forthe body plan of the developing embryo. For example,example, BMP4BMP4 and its inhibitorsand its inhibitors nogginnoggin andand chordinchordin help regulate polarity of the embryohelp regulate polarity of the embryo (i.e. back to front patterning).(i.e. back to front patterning). www.indiandentalacademy.comwww.indiandentalacademy.com
    138. 138. Mutations in BMPs and their inhibitorsMutations in BMPs and their inhibitors (such as(such as sclerostinsclerostin)) are associated with aare associated with a number of human disorders which affectnumber of human disorders which affect the skeleton.the skeleton. www.indiandentalacademy.comwww.indiandentalacademy.com
    139. 139. Tabin and co-workers set out to understandTabin and co-workers set out to understand how such morphological variations mighthow such morphological variations might arise due to BMPs.arise due to BMPs. (2004)(2004) www.indiandentalacademy.comwww.indiandentalacademy.com
    140. 140. They evaluated two finch species - the groundThey evaluated two finch species - the ground and cactus finches - that represent theand cactus finches - that represent the extremes in Galapagos finch beakextremes in Galapagos finch beak morphology (Grant, 1986 ).morphology (Grant, 1986 ). www.indiandentalacademy.comwww.indiandentalacademy.com
    141. 141. At the time when ground and cactus finchAt the time when ground and cactus finch embryos appear similar, in situ hybridizationembryos appear similar, in situ hybridization analyses by these investigators revealed aanalyses by these investigators revealed a difference in the patterns ofdifference in the patterns of Bmp4Bmp4 expression.expression. www.indiandentalacademy.comwww.indiandentalacademy.com
    142. 142. www.indiandentalacademy.comwww.indiandentalacademy.com
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    144. 144. Epithelial contribution toEpithelial contribution to craniofacial patterningcraniofacial patterning www.indiandentalacademy.comwww.indiandentalacademy.com
    145. 145. Neural andNeural and surfacesurface ectoderm:ectoderm: patterningpatterning the middlethe middle and upperand upper faceface www.indiandentalacademy.comwww.indiandentalacademy.com
    146. 146. When regions of facial ectoderm areWhen regions of facial ectoderm are transplanted to ectopic sites in the avian face,transplanted to ectopic sites in the avian face, the developmental fate of underlying frontonasalthe developmental fate of underlying frontonasal neural crest cells is altered and the result is aneural crest cells is altered and the result is a duplication of upper beak structures (Hu et al.,duplication of upper beak structures (Hu et al., 20032003 ).). This same bit of facial ectoderm can elicit similarThis same bit of facial ectoderm can elicit similar duplications when transplanted into the first,duplications when transplanted into the first, Hox-negative, arch, but has no effect whenHox-negative, arch, but has no effect when transplanted into the second, Hox-positive, archtransplanted into the second, Hox-positive, arch (Hu et al., 2003(Hu et al., 2003 ).). www.indiandentalacademy.comwww.indiandentalacademy.com
    147. 147. This result indirectly illustrates how neuralThis result indirectly illustrates how neural crest plasticity is balanced against a `pre-crest plasticity is balanced against a `pre- pattern', owing in no small part to thepattern', owing in no small part to the expression of Hox genes in the facialexpression of Hox genes in the facial tissues (Creuzet et al., 2002tissues (Creuzet et al., 2002 ).). What types of signals imbue this facialWhat types of signals imbue this facial ectoderm with the ability to re-specify theectoderm with the ability to re-specify the fates of neural crest cells?fates of neural crest cells? www.indiandentalacademy.comwww.indiandentalacademy.com
    148. 148. BothBoth ShhShh andand Fgf8Fgf8 are expressed in thisare expressed in this region of tissue, but whether they are theregion of tissue, but whether they are the molecules responsible for achieving thismolecules responsible for achieving this effect, or simply molecular markers of aneffect, or simply molecular markers of an important boundary domain in the face,important boundary domain in the face, remains to be determined.remains to be determined. Neural ectoderm is also a source ofNeural ectoderm is also a source of patterning information for the middle andpatterning information for the middle and upper face, as has recently been shown inupper face, as has recently been shown in a series of experiments conducted ina series of experiments conducted in zebrafish.zebrafish. www.indiandentalacademy.comwww.indiandentalacademy.com
    149. 149. In these experiments, it was found thatIn these experiments, it was found that Shh emanating from anterior ventralShh emanating from anterior ventral neuroectoderm directly patterned theneuroectoderm directly patterned the ventral surface ectoderm, without requiringventral surface ectoderm, without requiring an intermediate signal generated byan intermediate signal generated by neural crest.neural crest. The loss of neuroectodermal ShhThe loss of neuroectodermal Shh prevented neural crest cells fromprevented neural crest cells from aggregating into condensations andaggregating into condensations and eventually from forming skeletal elements.eventually from forming skeletal elements. www.indiandentalacademy.comwww.indiandentalacademy.com
    150. 150. THANK YOUTHANK YOU www.indiandentalacademy.comwww.indiandentalacademy.com
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    157. 157. Preview of next seminar:Preview of next seminar: Molecular mediators of craniofacial morphogenesisMolecular mediators of craniofacial morphogenesis HOX genesHOX genes Epithelial contribution to craniofacial patterningEpithelial contribution to craniofacial patterning Oral ectoderm and tooth patterningOral ectoderm and tooth patterning Pharyngeal endoderm and arch patterningPharyngeal endoderm and arch patterning Neural and surface ectoderm: patterning the middle andNeural and surface ectoderm: patterning the middle and upper faceupper face Patterning of the jawsPatterning of the jaws MaxillaMaxilla MandibleMandible palatepalate www.indiandentalacademy.comwww.indiandentalacademy.com
    158. 158. THANK YOU . . .THANK YOU . . . www.indiandentalacademy.comwww.indiandentalacademy.com
    159. 159. At the time when ground and cactus finch embryos appear similar,At the time when ground and cactus finch embryos appear similar, in situ hybridization analyses by these investigators revealed ain situ hybridization analyses by these investigators revealed a difference in the patterns ofdifference in the patterns of Bmp4Bmp4 expression (Abzhanov et al.,expression (Abzhanov et al., 20042004 ) (see) (see Fig. 4Fig. 4). To test experimentally whether spatial and). To test experimentally whether spatial and temporal changes intemporal changes in Bmp4Bmp4 expression could account for the relativeexpression could account for the relative size and shape differences in these finches' beaks, the investigatorssize and shape differences in these finches' beaks, the investigators mis-expressedmis-expressed Bmp4Bmp4 throughout the mesenchyme of a chickthroughout the mesenchyme of a chick frontonasal prominence (frontonasal prominence (Fig. 4DFig. 4D). This misexpression converted the). This misexpression converted the narrow short chick beak into a much broader bigger beak thatnarrow short chick beak into a much broader bigger beak that resembled that of the large ground finch (Abzhanov et al., 2004resembled that of the large ground finch (Abzhanov et al., 2004 ) () ( Fig. 4DFig. 4D).). www.indiandentalacademy.comwww.indiandentalacademy.com
    160. 160. Vertebrates exhibit a marvelous range of craniofacialVertebrates exhibit a marvelous range of craniofacial features that are designed to fit specialized niches andfeatures that are designed to fit specialized niches and behaviors.behaviors. These postnatal facial features are immediately obvious,These postnatal facial features are immediately obvious, but during the embryonic period, vertebrate faces lookbut during the embryonic period, vertebrate faces look remarkably similar (Haeckel, 1897remarkably similar (Haeckel, 1897 ).). The proteins that establish this basic blueprint of theThe proteins that establish this basic blueprint of the craniofacial region are still unidentified but likelycraniofacial region are still unidentified but likely candidates are those same molecules that establishcandidates are those same molecules that establish other developmental axes in vertebrates andother developmental axes in vertebrates and invertebrates: Hedgehog and Wnt proteins, andinvertebrates: Hedgehog and Wnt proteins, and members of the Bmp and Fgf families. Some newmembers of the Bmp and Fgf families. Some new studies have begun to explore how different species usestudies have begun to explore how different species use these pathways to create distinctive facial features.these pathways to create distinctive facial features. www.indiandentalacademy.comwww.indiandentalacademy.com
    161. 161. In the Galapagos finches, Darwin had noted that `aIn the Galapagos finches, Darwin had noted that `a nearly perfect gradation may be traced from a beaknearly perfect gradation may be traced from a beak extraordinarily thick to one so fine that it may beextraordinarily thick to one so fine that it may be compared with that of a warbler.' (Darwin, 1859compared with that of a warbler.' (Darwin, 1859 ). We). We now know that these species-specific morphologicalnow know that these species-specific morphological variations are evident during embryogenesis, and arevariations are evident during embryogenesis, and are first evident around Hamburger and Hamiltonfirst evident around Hamburger and Hamilton (Hamburger and Hamilton, 1951(Hamburger and Hamilton, 1951 ) stage 22 (S.) stage 22 (S. Brugmann and J.A.H., unpublished). Prior to that time,Brugmann and J.A.H., unpublished). Prior to that time, the faces of different avian species are indistinguishablethe faces of different avian species are indistinguishable from one another (Schneider and Helms, 2003from one another (Schneider and Helms, 2003 ). Tabin). Tabin and co-workers set out to understand how suchand co-workers set out to understand how such morphological variations might arise.morphological variations might arise. www.indiandentalacademy.comwww.indiandentalacademy.com
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    168. 168. Epithelial contribution toEpithelial contribution to craniofacial patterningcraniofacial patterning www.indiandentalacademy.comwww.indiandentalacademy.com
    169. 169. PRE-NATAL CRANIOFACIALPRE-NATAL CRANIOFACIAL MORPHOGENESISMORPHOGENESIS www.indiandentalacademy.comwww.indiandentalacademy.com
    170. 170. Basic research concerning craniofacialBasic research concerning craniofacial development runs along 2 pathwaysdevelopment runs along 2 pathways namely the molecular and thenamely the molecular and the morphometric. This gap will now bemorphometric. This gap will now be bridged in the initial part if this seminarbridged in the initial part if this seminar www.indiandentalacademy.comwww.indiandentalacademy.com
    171. 171. Pre natal craniofacialPre natal craniofacial morphogenesis : 4-D visualizationmorphogenesis : 4-D visualization of morphogenetic processesof morphogenetic processes Orthod Craniofacial Res 6( sppl. 1), 2003;89-Orthod Craniofacial Res 6( sppl. 1), 2003;89- 9494 www.indiandentalacademy.comwww.indiandentalacademy.com
    172. 172. Using histological sections of human fetusesUsing histological sections of human fetuses computer aided 3-D reconstuctions werecomputer aided 3-D reconstuctions were made with special focus given to allmade with special focus given to all anatomical structures of orofacial region ofanatomical structures of orofacial region of the orofacial region of the growing head.the orofacial region of the growing head. www.indiandentalacademy.comwww.indiandentalacademy.com
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    185. 185. The hard tissues like the bones,The hard tissues like the bones, cartilages, and teeth, play manycartilages, and teeth, play many essential roles for our survival.essential roles for our survival. Calvarial and cranial baseCalvarial and cranial base bones protect the brain and thebones protect the brain and the sense organs from externalsense organs from external shocks. Three small bones inshocks. Three small bones in the inner ear are needed for usthe inner ear are needed for us to hear. Jaws allow us to talkto hear. Jaws allow us to talk and along with the teeth allowand along with the teeth allow us to chew.us to chew. www.indiandentalacademy.comwww.indiandentalacademy.com
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    188. 188. www.indiandentalacademy.comwww.indiandentalacademy.com Thank youThank you For more details please visitFor more details please visit www.indiandentalacademy.comwww.indiandentalacademy.com

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