signalling molecules

• Signalling molecules

  Inter-cellular signalling mechanism that promote cell growth, differentiation and maturation
• Facial development

  • Spatial and temporal molecular control
  • Genes and regulatory gene products that control patterning during embryogenesis
  • Issues with any one of these may have an impact on normal facial development
• Recent sequencing of the human genome is revealing the template of the directional signals and morphogenetic elements guiding development of the embryo
• 17,000 genes have been identified in contributing to craniofacial development

  
• Complexities of cellular differentiation, histogenesis, tissue migration, apoptosis, melding and fusion of folds, and prominences in creating the human face are being elucidated by identifying genes, transcription factors, and signalling pathways that are responsible for the phenotypic expression of facial development
• Dysmorphology will potentially be anticipated and possibly biomimetically controlled by genetic and growth factor intervention rather than by post hoc treatment by mechanical means
• Early development

  1. Proliferation

  2. Migration

  3. Differentiation
• Interactions between cells and tissues

  Central mechanism regulating development of all multicellular organisms
• Interactions

  Complex signalling networks composed of signals, their receptors and transcriptional control systems
• Morphogen gradients

  Positional cues for cells during development; establish cell signalling networks to control gene expression
• Embryogenesis

  1. Fertilisation

  2. Induction, competence, differentiation

  3. Formation of the three layered embryo

  4. Formation of neural crest cells

  5. Folding of the embryo
• Growth factors

  Signalling molecules that promote cell growth, differentiation and maturation
• Growth factors are produced as early as the 2 cell stage
• Growth factors

  • TGFβ
  • Hedgehog/SHH
  • Wingless/WNT
  • EGF
  • FGF
  • BMP
  • retinoic acid
• Homeobox genes

  Key genes that initiate primary germ layers, neural plate folding and further subdivision
• Homeobox

  A DNA sequence found within genes that are involved in the regulation of patterns of anatomical development (morphogenesis) in animals, fungi and plants

  
• Homeodomain

  Protein domain encoded by the homeobox, which when expressed can bind DNA (sequence-specific)
• Homeobox transcription factors typically switch on cascades of other genes
• Hox genes

  A group of related genes that determine the basic structure and orientation of an organism
• Hox genes are critical for proper placement of segment structures of animals during early embryonic development
• Most Hox genes are linked together in sequential clusters
• Hox genes are organized on the cluster in the order of expression pattern along the cephalo-caudal (head to tail) axis of the organism
• Hox proteins

  Transcription factors, capable of binding to specific nucleotide sequences on the DNA called enhancers where they either activate or repress genes
• The same Hox protein can act as a repressor at one gene and an activator at another
• Hox genes

  Act at many levels within developmental gene hierarchies, regulating genes that in turn regulate large networks of other genes, directly regulating "realisator" genes or "effector" genes, and promoting cell division, cell adhesion, apoptosis, and cell migration
• Transcription factor cascade

  1. Growth factors activate Hox genes; Hox genes activate realisator genes that cause the segments in the developing embryo to differentiate

  2. Positive and negative feedback loops
• Morphogenetic fields

  A group of cells able to respond to discrete, localized biochemical signals leading to the development of specific morphological structures or organs
• The spatial and temporal extent of the embryonic fields are dynamic, and within the field is a collection of interacting cells out of which a particular organ is formed</b>
• Cells within a given morphogenetic field are constrained, but their specific cellular programming is flexible
• Hox gene clusters in humans

  • HOXA (chromosome 7)
  • HOXB (chromosome 17)
  • HOXC (chromosome 12)
  • HOXD (chromosome 2)
• Morphogenetic fields

  • Spatial and temporal extent are dynamic
  • Within the field is a collection of interacting cells out of which a particular organ is formed
  • Cells within a given field are constrained
  • Specific cellular programming of individual cells in a field is flexible
• Other proteins containing a homeodomain

  • ADNP; ALX1; ALX3; ALX4; ARGFX; ARX
  • BARHL1; BARHL2; BARX1; BARX2; BSX
  • CDX1; CDX2; CDX4; CRX; CUTL1; CUTL2
  • DBX1; DBX2; DLX1; DLX2; DLX3; DLX4; DLX5; DLX6; DMBX1; DPRX; DRGX; DUX1; DUX2; DUX3; DUX4; DUX4L2; DUX4L3; DUX4L4; DUX4L5; DUX4L6; DUX4L7; DUX4L9; DUX5; DUXA
  • EMX1; EMX2; EN1; EN2; ESX1L; EVX1; EVX2
  • GBX1; GBX2; GSC; GSC2; GSX1; GSX2
  • HDX; HESX1; HHEX; HLX1; HMBOX1; HMX1; HMX2; HMX3; HNF1A; HNF1B; HOMEZ; HOPX
  • IRX1; IRX2; IRX3; IRX4; IRX5; IRX6; ISL1; ISL2; ISX
  • LASS2; LASS3; LASS4; LASS5; LASS6; LBX1; LBX2; LHX1; LHX2; LHX3; LHX4; LHX5; LHX6; LHX8; LHX9; LMX1A; LMX1B
  • MEIS1; MEIS2; MEIS3; MEOX1; MEOX2; MIXL1; MKX; MNX1; MSX1; MSX2
  • NANOG; NANOGP1; NANOGP8; NKX2-1; NKX2-2; NKX2-3; NKX2-4; NKX2-5; NKX2-8; NKX3-1; NKX3-2; NKX6-1; NKX6-2; NKX6-3; NOBOX; NOTO
  • ONECUT1; ONECUT2; ONECUT3; OTP; OTX1; OTX2
  • PAX3; PAX4; PAX6; PAX7; PBX1; PBX2; PBX3; PBX4; PDX1; PHOX2A; PHOX2B; PITX1; PITX2; PITX3; PKNOX1; PKNOX2; POU1F1; POU2F1; POU2F2; POU2F3; POU3F1; POU3F2; POU3F3; POU3F4; POU4F1; POU4F2; POU4F3; POU5F1; POU5F1P1; POU5F1P4; POU5F2; POU6F1; POU6F2; PROP1; PRRX1; PRRX2
  • RAX; RAX2; RHOXF1; RHOXF2
  • SATB1; SATB2; SEBOX; SHOX; SHOX2; SIX1; SIX2; SIX3; SIX4; SIX5; SIX6
  • TGIF1; TGIF2; TGIF2LX; TGIF2LY; TLX1; TLX2; TLX3; TSHZ1; TSHZ2; TSHZ3
  • UNCX; VAX1; VAX2; VENTX; VSX1; VSX2
  • ZEB1; ZEB2; ZFHX2; ZFHX3; ZFHX4; ZHX1
• Signalling factors and transcription factors expressed in the developing face

  • Wnt-5a
  • Activin baa
  • En protein
  • Dlx-1a, 2a
  • Msx-1a,b and 2b
  • Otx-2a
  • Pax-3a,b and 7a
  • Barx-1 and 2
  • AP-2a
  • Gli-2a and 3a
  • twista,b
  • Bmp-2, 4a, 5a and 7a
  • EGF
  • ET-1a
  • FGF1, 2,4, 5, 8 and 12
  • PDGF-a
  • Jagged 1b and 2a
  • Dlx-1–6 (1a2a)
  • En-2
  • GH-6
  • Gsc-1a
  • Mhoxa (Prx-1)
  • Gli-1, 2aand 3a
  • Pax-1a
  • TGFa
  • TGFb1, 2a and 3a
  • Wnt-5a, 10a,10b, 11
  • Pax-3a,b, 7a, 6a,b
  • Ptx-1
  • Reigb
  • S8
  • Tlx-1 (Hox11)
  • Shha,b
  • Otx-2a
• With the increasing identification of growth factors, genes, and chromosomes responsible for development of the face, clinical geneticists and orthodontists are now in a better position to advise parents of the ultimate outcome of prognosis of various dentofacial malformations and malocclusions of their progeny.
• The hope of biomimetic intervention by genetic engineering and molecular factor signalling utilization in controlling growth, once considered only a remote possibility, is now becoming ever more realistic, as the introduction of altered genomes becomes more feasible.