Tooth

Development

Zhaoming Wu
zhaomin9@[Link]
Anticipated learning outcomes
• Understand the characteristics of different stages of tooth
development
• Describe the structures of a tooth germ at different morphological
stages
• Describe the cells involved in tooth development and their origins
• Describe the mineralization of enamel and dentin
Evolutionary origin of the vertebrate tooth
• Still under debate, two major
theories
• ”Outside-in” theory:
• Teeth evolved from ectoderm-derived
skin denticles that folded in and
integrated into the mouth Tooth-like structures (dermal denticles) on the
surface of shark skin

• “Inside-out” theory:
• Teeth originated from endoderm
pharyngeal teeth of jawless vertebrates
and moved into the oral cavity with the
evolution of the jaws
Pharyngeal teeth of a lamprey

Jheon et al, 2012 “From molecules to mastication: the development and evolution of teeth”
Before tooth development: from gastrulation
to tooth initiation
First Pharyngeal arch: where most of the
tooth development take place (except for
the upper incisors, which are from the
frontonasal process)
Stages of tooth development

Thesleff 2014
Initiation: primary epithelial band
• Earliest morphological sign of tooth
development
• A thickening of the oral epithelium
• Continuous, U shaped
• Give rise to dental lamina and
vestibular lamina soon after its
formation

Schematic representation of the

primary epithelial band within
the embryonic oral cavity
Initiation: dental lamina

A continuous, U shaped epithelial thickening

arise from the primary epithelial band.

Schour 1929
 Morphogenesis: dental placode
Along the U-shaped continuous dental lamina, epithelium thickenings form at sites of future
tooth development

Balic 2018

Dental lamina: continuous, U shape

3D rendering of discrete epithelial thickenings arise from the dental lamina Dental placode: discrete
 Morphogenesis: bud stage
From dental placode, further epithelial proliferation and invagination result in bud-like structures.
Ectomesenchymal cell condensation form around the tooth bud.

A: Dental lamina, which connects to the oral epithelium

B: Tooth bud
C: Mesenchymal condensation
 EK: enamel knot
Morphogenesis: Cap stage IEE: inner enamel epithelium
OEE: outer enamel epithelium

Dental papilla: condensed

dental mesenchyme below the
enamel organ.
The enamel organ will for the
OEE enamel, the dental papilla will
form dentine and pulp
Enamel organ The dental follicle (dental sac)
will form the periodontium.
EK
Dental follicle Enamel knot: none-dividing
(dental sac)
IEE signaling centre of the IEE
Dental papilla

Early cap stage

Expression of Fgf4 gene,

along with many other
Late cap stage signalling genes from the EK
 secondary

Morphogenesis/differentiation: bell stage

Dental lamina

• The enamel organ continues to grow larger,

SR the IEE fold to the shape of the future tooth
Stratified crown
reticulum • Cells from the IEE and dental papilla near
the secondary enamel knots start to
differentiate
DF
DP DF: dental follicle aka dental sac, will form the PDL,
cementum and alveola bone.
DP: dental papilla
SR: stellate reticulum, low cell density, rich in ECM
molecules such as hyaluronic acid and versican,
functions in mechanical protection and nutrition
recruitment.
Stratified reticulum, located between the SR and
IEE, work with IEE as a in the formation of enamel
 Secondary enamel knots and cusps formation
* *

• Cap stage teeth have one primary enamel knot, bell stage teeth
have multiple secondary enamel knots (SEK).
• SEKs serve as signalling centres to induce the folding of the IEE * *
and differentiation of IEE and adjacent dental papilla cells
• Number of SEKs = Number of cusps

Dspp: marks ameloblast and odontoblast differentiation * Future cusps

Amelogenin: marks ameloblast differentiation
 Matrix secretion

The IEE differentiate into ameloblasts, which regulate the formation of enamel
The underlying dental papilla differentiate into odontoblast, which regulate the formation of dentin
Ameloblast and odontoblast induce the
differentiation of each other
1. Early differentiation of Ameloblast
triggers formation of the dentine.

2. Terminal differentiated
odontoblast secrete the first layer of
predentine matrix, which triggers
the terminal differentiation of
ameloblast.
 Amelogenesis - overview

Tomes’ process

1. Inner Enamel Epithelium

2. Differentiating ameloblasts grows taller
3. Pre-secretory ameloblasts send processes through the degenerating basement membrane
4. Secretory ameloblasts, secrete and retreat, Tomes’ process modulate protein secretion and enamel crystal growth
5. At the end of secretory stage, Tomes’ process disappear, enamel reaches full thickness
6. Basement membrane reappears, ameloblast go through transition where the proteins they secrete change
7. Maturation stage, the ameloblasts shift between ruffled and smooth-ended phases, their activities result in removal
of water and protein and influx of minerals
Amelogenesis - Inter-rod enamel

The relationship between Tomes’ processes

and enamel prism(rod) formation. R: enamel rod
IR: inter-rod enamel
• Each ameloblast’s Tomes’ process modulate the formation of one enamel rod.
• Enamel crystallites form near the cellular junction are interrod enamel
• Inter-rod enamel has the same composition as enamel rod, but differs in crystal orientation
 Dentinogenesis

Odontoblast process

1 Ameloblast begins to differentiate first.

2 Peripheral dental papilla cells divide
3 Acting on a signal from the ameloblast, the preodontoblasts begin to differentiate.
4 Synthetic organelles increase in size and number to prepare for secretion
5 Odontoblast processes begin to form. One odontoblast process becomes enlarged and begins to secrete matrix.
6 The odontoblast retreats as matrix is laid down, leaving behind a single main process. Once a narrow layer of
matrix is laid down mineralisation commences.
7 Once the first layer of dentine is laid down the differentiated ameloblast begins to deposit matrix.
Tooth development - Eruption
 Root formation, showing root
sheath and epithelial diaphragm.
Tooth root development A The fusion of OEE with IEE result
in epithelial root sheath formation.

B Later stage of root sheath

development.
Root dentin has formed below the
cervical enamel on the surface of
the pulp organ.

As the root is being formed, the

↑ upper part of the root sheath

degenerates, leaving behind
cervical groups of epithelial cells –
losp epithelial cell rests of Mallasez
LIEE-DEE
(ERM)
junction
↓
Hertwig's Epithelia
Root Sheath
Cell rests of Malassez
-
> Guide root shape >
-
(ERM)
Root Formation
• Cells in the dental follicle give rise
to cementoblasts which form
cementum the covers the root

dentine
dentine

alveolar bone
• Periodontal ligaments are formed
and inserted into the cementum
and alveolar bone
• Root formation continues after
tooth eruption cementum
 Tooth root morphogenesis

HERS: Hertwig rooth sheath

Tooth development – Secondary tooth
development
Tooth developmental defects – genetic
factors
• Amelogenesis imperfecta (e.g. AMEX)
• Dentinogenesis imperfecta (e.g. DSPP)
• Ectodermal dysplasia (e.g. EDA)
• Oligodontia (e.g. PAX9)
• Supernumerary teeth (e.g. RUNX2)

Upper: hypodontia
Lower: supernumerary teeth
X-linked hypohidrotic ectodermal dysplasia (HED)
• Oligodontia, sparse hair, severe
lack of sweat glands
• Mutations in the ectodysplasin
(Eda) pathway
Mouse model
• Eda regulate the enamel knots Dental phenotype of human patients
(Tabby: Eda
gene mutation)
formation during tooth
development

WT Fgf4 Tabby Fgf4

Red colour: Fgf4 (EK marker) expression.

Reduced size and number of enamel knots lead to smooth cusps
Amelogenesis imperfecta (AI)
• 2 types: hypoplastic AI (thin or
absence of enamel),
hypomineralised AI
• The later can further divide into
hypomaturation (incomplete
removal of protein from enamel
matrix) and hypocalcified AI
(insufficient calcium ions
transportation into the
developing enamel)
• Can be caused by mutations in
genes including AMELX, ENAM,
AMBN, KLK4, MMP20
Dentinogenesis imperfecta

• With or without bone

defects
• DSPP mutations are
often found in the
patients without
bone defects
• DSPP encodes a
protein that is
specifically found in
the dentine matrix
Tooth developmental defects – environmental
factors
• Chemical exposure (Tetracycline,
fluorides, dioxins)
• Severe malnutrition
• Severe infections
• Maternal diabetes Tetracycline teeth

• Neonatal asphyxia

Dental fluorosis
 Tooth regeneration – can we unlocking the infinite
tooth regeneration potential?
• Human have two sets
of teeth
• Alligator, however,
Alligators maintain their dental
have infinite sets of lamina throughout their lives
teeth
• Because their dental
lamina with a stem
cell niche retain
throughout their lives Alligator tooth cycle: once the
functional tooth (f) is lost, the
replacement tooth (r) takes over, After development of 2 sets of
and a new replacement tooth will teeth the dental lamina is gone
form from the dental lamina (dl)
Summary
• Tooth development is driven by interactions between dental epithelium
(enamel organ) and dental mesenchyme (dental papilla)
• The dental epithelium comes from oral ectoderm, dental mesenchyme
comes from neural crest (which is also from ectoderm)
• The major morphological stages of tooth germ development: bud, cap, bell
(early bell, late bell)
• Enamel knots are signalling centres regulating the morphogenesis and
differentiation of the tooth
• Ameloblasts and odontoblasts are the key cells responsible for the
formation of enamel and dentine, respectively.
• Both genetic and environmental factors can cause tooth developmental
defects
Recommended textbook:
• Ten Cate's Oral Histology: Development, Structure, and Function