5 Molecular & Genetic Basis of Tooth Development Flashcards
Final fate of NCC?
Odontoblasts or cementoblasts via ectomesenchymal cells.
Teeth are only developed in…?
the 1st branchial arch`
Stem cells (ie NCCs) can…
replicate (via asymmetric division) or differentiate into many cell types.
NCC (4th germ layer) + ectoderm, endoderm, mesoderm. Role of each “germ”?
Ectoderm = regulates NCC cells during morphogenesis, controls position, size, and shape of organs. Mesoderm = provides environment. Endoderm = develops pharyngeal pouch-generated organs (thyroid, parathyroid, and thymus)
1. NCCs form well-organized migratory streams to the branchial arches. BA?
Via hindbrain rhmobomeres. *1st BA: r 1, 2 2nd BA: r 4 3rd BA: r 6, 7 r 3 & 5 degenerate.
1. NCCs form well-organized migratory streams to the branchial arches. CN?
*CN V: r 1-3
CN VII: r4-5
CN IX: r6-7
2. NCCs in each migratory stream express specific Hox gene codes. Def/role?
Hox genes = a group of homeobox genes, which possess a unique homeobox (DNA sequence) –> homeodomain (protein segment) which acts as TF.
2. NCCs in each migratory stream express specific Hox gene codes. Which BAs express Hox genes?
1st BA is Hox-free (carry genes but don’t express them).
2nd BA begins Hox expression
3. Within each BA, specific Dlx genes are expressed to produce regional differences (ie b/w maxilla and mandible). Def/role?
Dlx = another homeobox gene –> TF.
7 members of family.
Dlx 4, 7, 8, 9 are same.
3. BA 1 Dlx 1/2?
maxillary (proximal) process
Double mutants lack all maxillary molars (mandibular molars unaffected)
Proper development of maxillary/proximal process requires?
Dlx 1/2
3. BA 1 Dlx 5/6?
mandibular (distal) process
-/- mutants develop lower jaws that are mirror images of upper jaws
Proper development of mandibular/distal process requires?
Dlx 5/6
*Among cells required for tooth development, which ones have an NCC origin?
Odontoblasts and cementoblasts (via ectomesenchyme). NOT ameloblasts.
*NCCs migrated to the 1st BA are from which hindbrain rhombmeres?
r 1 + 2
*Which homeobox gene differentiates NCCs migrated to different BA?
Hox genes
*Which homeobox gene differentiates development of the maxillary and mandibular processes within the first BA?
Dlx genes
max: Dlx 1+2
mand: Dlx 5+6
Origin of tissue-tissue interactions?
Initiated by epithelium, followed by epithelium-mesenchyme interaction through the entire process of tooth development.
Origins of enamel and dentin?
Ectoderm –> epithelium –> ameloblasts/enamel
NCC/mesoderm –> mesenchyme –> odontoblasts –> dentin
Ectoderm-Derived Epithelium Signaling Pathways - 4 molecule names?
BMP: bone morphogenic protein
FGF: fibroblast growth factor
Wnt: wingless (drosophila) & int (mouse)
SHH: sonic hedge hog
Ectoderm-Derived Epithelium Signaling Pathways - mechanism of action?
Molecules bind membrane receptors –> impact gene regulation (via varied intracellular pathways). Also important for ectodermal organs (ie hair, nails glands)
Enamel knots definition
Epithelial aggregates function as signal centers for tooth morphogenesis & odontoblast differentiation.
Primary enamel knots
Bud –> cap transition in ALL teeth.
Stimulate proliferation of adjacent cells.
Disappear by apoptosis.
Secondary enamel knots
Determine number & location of molar cusps (NOT in incisors).
Stimulate terminal differentiation of odontoblasts.
Signaling molecules in enamel knots?
FGF = cusp activator
BMP, SHH = cusp inhibitor
to regulate formation of inter-cusp distance.
Cranial CNNs contribute to…
Formation of all tooth structures (dentin, cementum, pulp, PDL, but NOT enamel)
Mesenchyme Signaling Molecules?
Signaling molecules: BMP, FGF, Wnt, inhibitors (but not SHH)
Transcription factors: Msx1/2, Dlx1/2, Pax9, Gli2/3, Runx2, Barx1, etc.
steps of development of a tooth crown
- initiation
- morphogenesis
- differentiation and mineralization
Tooth identify determination
Anterior (distal): BMP4 –> MSx 1/2
Posterior (proximal): FGF –> Barx1, Dlx2, Lhx6/7
Epithelium expresses…into mesenchyme?
Sema3A = serves as chemorepellant for axons, thus controlling the timing and patterning of tooth innervation
*What are the cell and tissue origins for tooth structures?
Most are mesenchyme (enamel is epithelium)
Ectoderm –> epithelium –> ameloblasts/enamel
NCC/mesoderm –> mesenchyme –> odontoblasts –> dentin
*What four major signaling molecules are produced by the epithelium?
BMP, FGF, Wnt, SHH
*What are the common transcription factors produced by the mesenchyme?
Transcription factors: Msx1/2, Dlx1/2, Pax9, Gli2/3, Runx2, Barx1, etc.
What are the common signaling molecules produced by the mesenchyme?
Signaling molecules: BMP, FGF, Wnt, inhibitors (but not SHH)
*What are the main characteristics and functions of the two sets of enamel knots?
1˚: bud –> cap transition for all teeth.
2˚: location and number of cusps for molars
*At the cellular and molecular level, crown development is divided into what 3 stages?
IM DM
- Initiation
- Morphogenesis
- Differentiation & Mineralization
*Innervation of tooth is from which NC, and when do the nerve fibers first enter the pulp area?
CN V, enters after the start of enamel formation
HERS
After crown development nearly complete, epithelial root sheath grows apically between two mesenchymal regions (dental papilla & follicle).
Epithelium and root development?
No enamel in root, but induction from epithelium is required for root development.
HERS induces…
HERS induces dental papilla cells to differentiate into odontoblasts.
HERS uses…?
Differentiation via lamini-5 and TGF-beta.
Nfic?
Nuclear factor Ic
Essential for root dentin (along with HERS), but not crown dentin formation
Cementum formation starts when…
HERS (epithelial) and dental follicle (mesenchyme) cells are in close proximity
Epithelium-Mesenchyme Interaction during Root Development
HERS: TGF-b, Nfic, insulin-like GF, Wnts, FGF
Mesenchyme: BMP, FGF
Some overlap with crown develpment
Two mechanisms to root cementum formation?
1st: directly from dental follicle
2nd: HERS “trans-differnetiated” into cementoblasts.
Contributions of HERS to root development
- HERS do not –> ameloblasts/enamel.
- HERS do not respond to signals from the mesenchyme and differentiate into ameloblasts.
- Induce diff. of odontoblasts
- Induce diff. of cementoblasts, OR HERS cells may transdifferentiate into cementoblasts.
- Determine # of roots
Fates of HERS
- Become epithelial rest of Malassez
- Apoptosis
- Incorporated into the cementum front
- E-M transformation
- Migration to PDL
- Differentiation into ameloblasts
*What are the tissue and cell origins for root dentin and cementum?
Mostly mesenchyme - some cementum from HERS (epi) via transdifferentation
*Is epithelium required to induce the formation of odontoblasts to root dentin and cementumblasts to cementum?
Yes! Epi required, even though no enamel in root.
*Are molecules involed in E-M interaction for root development the same as those involved in crown development?
No, some overlap
What can happen to HERS after root development?
Multiple possibilities (induce, transdifferentiate, apoptosis)
ectodermal dysplasia syndrom
2+ ectoderm structures
mutation of TF p63 (critical for FGF, BMP, SHH epi-mes interaction)
Msx1 mutation
No max premolars, mand 2nd premolars
G–>C transversion (arginine –> proline)
TF in mesenchyme
Mutation in homeodomain region
Pax9 mutation
no molar development
guanine insertion
TF in mesenchyme
Mutation in DNA-binding domain
Axin2 mutation
8+ perm teeth underdevelopd Missense (C-->T), insertion (G) Premature stop codon Disrupts Wnt signaling to mesenchyme Colorectal polyps and cancer
EDA mutation
multiple missing anterior teeth X-linked dominant Missense C--G ==> Q to E substitution in EDA Transmembrane signaling molecule TNF pathway
Theories of etiology of supernumerary teeth
tooth germ dichotomy
genetic and environmental factors
System conditions –> supernumerary teeth
Cleidocranial dysplasia
Familial adenomatous polyposis (Gardner’s syndrome)
Cleidocranial Dysplasia
Supernumerary, delayed/impact perm.
Runx2 TF mutation
Gardner’s Sydnrome
Supernumerary, impact, dentigerous teeth
Apc mutation through Wnt signaling pathway
Apc loss-of-function, B-catenin gain-of-function
*Gene mutations related to missing teeth?
TF: Msx1, Pax9, p63 (BMP, FGF, SHH)
Signal: Axin2 (via Wnt), EDA (via TNF)
*Gene mutations related to supernumerary?
TF: Runx2
Singal: Apc (via Wnt)
