Palatogenesis.txt

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emm64
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120883
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Palatogenesis.txt
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2011-12-05 02:03:41
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GDA Palatogenesis
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GDA Palatogenesis
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  1. Cleft Causes
    interference with shelf elevation, attachment, or fusion.
  2. Shelf elevation
    • brought about by mesenchymal proliferation and changes in the ECM induced by growth factors such as TGF-βs. Crucial ECM molecules are collagens, proteoglycans, and glycosaminoglycans.
    • Shelf attachment depends on specific differentiation of the epithelium involving TGF-β3, sonic hedgehog, and WNT signaling, and correct expression of epithelial adhesion molecules such as E-cadherin.
    • The final fusion requires epithelial apoptosis and epithelium-to-mesenchyme transformation regulated by TGF-β and WNT proteins
  3. somites
    Segmented part of the embryo that will form skeletal tissue, limbs
  4. neuroectoderm
    • forms into a neural plate
    • plate thickens through proliferation (cell division) and invaginates in the center – forms the neural groove
    • groove deepens and becomes surrounded by the neural folds
    • groove eventually forms the neural tube - brain, spinal cord, retina
  5. Cranial NC cells
    • develop following migration of cells from the neuroectoderm of the developing forebrain, midbrain and hindbrain
    • more rostral CNC cells give rise to the frontonasal skeleton and parts of the skull vault
    • more posterior CNCs migrate into the branchial arches cartilage and bones of the orofacial region – including the maxilla and mandible – plus the palate
    • cranial parasympathetic ganglia
    • skeletal muscles of the face and jaw are mesodermal in origin
  6. 1st branchial arch
    • mandibular arch
    • around 24 days forms the maxillary and mandibular processes
    • cartilage = Meckel’s
  7. second branchial arch
    • (hyoid arch) - hyoid bone, part of the temporal bone
    • cartilage = Reichert’s cartilage
    • the mesoderm of this arch will form the muscles of facial expression, the middle ear muscles
  8. 3, 4, 6 branchial arches
    • third arch –tongue
    • fourth arch –tongue, most of the laryngeal cartilages; fifth arch – becomes incorporated into the fourth
    • sixth arch – most of the laryngeal cartilages
  9. 5 face primordia
    • which develop during week 4 and fuse during weeks 5 through 8
    • primordia = ectodermal swellings or prominences that are filled with mesodermal and neural crest cells
    • primordia surround the primitive oral cavity – the stomatodeum
    • produced via proliferation of mesenchymal cells beneath the surface ectoderm
    • frontonasal prominence
    • mandibular prominences (2) – from branchial arch #1
    • maxillary prominences (2) – from branchial arch #1
  10. sixth week
    • primitive nasal cavities separated by primitive nasal septum and from the primitive oral cavity by the primary palate
    • development of two lateral palatal shelves behind the primary palate
  11. seventh week
    • oral cavity fills with the developing tongue
    • tongue withdraws from between the shelves-necessary for shelf fusion
    • growth of palatal shelves continues
    • shelves now lie vertically
  12. eighth week
    • stomatodeum enlargens
    • tongue drops
    • palatal shelves become horizontal
    • shelves grow medially and begin to fuse
  13. role of hyaluronan
    • one of many GAGs that change in amount during palatogenesis
    • GAGs decrease slightly prior to elevation and rise significantly after elevation – more pronounced in the anterior regions of the fusing palate
    • this rise coincides with palatal fusion
    • specific role for hyaluronan?
    • HA can bind up to 10 times its own weight in water – hydrostatic force? (Brinkley and Morris-Wiman 1987)
    • HA levels are significantly increased in the shelves immediately prior to elevation
    • enzymes associated with HA synthesis and HA binding ECM proteins versican and hyaluronectin can be found in elevating shelves
    • HA digestion prevents shelf elevation
    • reduced weight HA also results in abnormal elevation
  14. week 9
    • shelves begin to fuse with each other upon contact – and with the secondary nasal septum
    • forms the definitive secondary palate
    • shelves also begin to fuse with the primary palate
    • separates the oral and nasal cavities
    • shelf fusion occurs between the epithelial cells at the medial edge of the elevating palatal shelves = medial edge epithelia (MEE)
    • shelf fusion requires adherence between the two MEEs
    • after contact between the MEEs – the MEE becomes the midline epithelium seam
  15. MEE adherence
    • palatal shelves “adhere” at the midline through a mixture of “sticky” glycoproteins
    • midline epithelial seam forms as epithelial cells attach via desmosomes
    • presence of desmoglein and desmocollin (transmembrane proteins) plus desmoplakin (plaque protein) during palate development (Mogass et al. 2000)
    • desmosomes accumulate just prior to shelf contact
    • role for other adhesion proteins likely
    • mutations in E-cadherin can result in cleft palate (Frebourg et al. 2006)
    • only the shelf epithelia adhere with each other – not with other epithelia in the area (e.g. tongue)
  16. Palatal Shelf Fusion
    • the midline epithelial seam must degenerate for fusion to occur
    • mechanism of degradation is controversial
    • 1. apoptosis within the seam? (Martinez-Alvarez et al.2000)
    • 2. migration of epithelial cells from the seam? (Jin and Ding 2006)
    • 3. epithelial transition into mesenchymal cells? (Vaziri Sani et al. 2005)
    • epithelio-mesenchymal transdifferentiation requires remodelling of the ECM
    • after degradation - the mesenchyme of both shelves becomes continuous
    • further differentiation of the mesenchymal cells produces the palatal processes of the maxilla and the palatine bone
    • epithelial-mesenchymal interaction is critical
    • “mixing” of migrating epithelial and mesenchymal cells within the seam region due to migration
    • direct mesenchyme to epithelial contact is not seen!
    • alternatively – loss of basement membrane allows for paracrine signaling by mesenchyme
    • nature of the signals made by the mesenchyme is not known
    • role of the ECM?
    • collagens
    • fusion is followed by ossification
    • from four centers of intramembranous ossification
    • one in each developing maxilla (palatine process)
    • one in each developing palatine bone
    • incomplete ossification in these centers – results in the transverse and medial palatine sutures
  17. twelfth week
    fusion of palatal processes is complete
  18. Primary palate
    • forms at the 6th week of development
    • separates the primitive nasal cavities (above) from the primitive oral cavity (below)
    • divides the stomatodeal chamber into a
    • primitive oral cavity (anterior to palate)
    • larger oronasal cavity (posterior to palate)
    • outgrowths of the intermaxillary segment into the oral cavity and their fusion results in the primary palate
  19. Secondary Palate
    • the larger oronasal cavity is bounded anteriorly by the primary palate and occupied by the developing tongue
    • only after the development of the secondary palate can oral and nasal cavities by distinguished
    • three outgrowths appear in the oral cavity around the 6/7th week of development
    • secondary nasal septum: 6th week
    • forms from another swelling of the frontonasal prominence
    • grows downward along the midline into the nasal cavity toward the tongue where it encounters the primary and secondary palates
    • two lateral palatine shelves: 6th week
    • develop from the maxillary processes
    • grow in toward the midline
  20. Palatal Shelf Fusion
    • the midline epithelial seam must degenerate for fusion to occur
    • mechanism of degradation is controversial
    • 1. apoptosis within the seam? (Martinez-Alvarez et al.2000)
    • 2. migration of epithelial cells from the seam? (Jin and Ding 2006)
    • 3. epithelial transition into mesenchymal cells? (Vaziri Sani et al. 2005)
    • epithelio-mesenchymal transdifferentiation requires remodelling of the ECM
    • after degradation - the mesenchyme of both shelves becomes continuous
    • further differentiation of the mesenchymal cells produces the palatal processes of the maxilla and the palatine bone
  21. Syndromic CL/P
    • genetically traceable
    • Numerous syndromes associated with syndromic CL/P
    • Nager
    • Van der Woude (IRF6)
    • Roberts (ESCO2)
    • Gorlin (Patched 1)
  22. TGFb3
    • numerous studies using deficient mice
    • control of downstream expression of MMPs & ECM remodelling
  23. IRF6
    • confirmed through many types of genetic analysis
    • SNP rs642961 identified in the enhancer of IRF6
    • IRF6 deficient mice – hyper-proliferation of epidermis resulting in cleft palate
  24. FGFR2
    • also FGFR1 and FGF8
    • FGFR2 associated with numerous craniofacial abnormalities – including craniosynostosis
  25. msx1 and BMP signaling (BMP4)
    • loss of function msx1 – CL/P
    • loss of function BMPR1A – CL/P
    • deficiency in BMP4 - cleft lip only
  26. Wnt/b-catenin signaling
    • new area of interest – Wnt signaling thought to be involved in normal palate and lip formation
    • targeted mutation of Wnt9 – CL/P
    • msx1 and msx2 may also be downstream factors

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