HEAD & NECK CME

ABBREVIATION KEY
AI ⫽ amelogenesis imperfecta
AMELX ⫽ amelogenin X-linked
protein coding gene
AXIN2 ⫽ axin-like protein or axis
inhibition protein
BARX1 ⫽ barH-like homeobox gene
BMP (2,4,7) ⫽ bone morphogenic
Review of the Embryology of the protein
CBFA1 ⫽ osteoblastic-specific
Teeth transcription factor
CSF-1 ⫽ colony-stimulating factor 1
DD ⫽ dentin dysplasia
P.M. Som and I. Miletich
DGI ⫽ dentinogenesis imperfecta
DIX1–2,3,5,6,7 ⫽ homeobox genes
DLX2 ⫽ distal-less homeobox
gene 2
DLX3 ⫽ DSPP ⫽ dentin
CME Credit sialophosphoprotein
The American Society of Neuroradiology (ASNR) is accredited by the Accreditation Council for Continuing Medical Education
EDA ⫽ ectodysplasin signaling
(ACCME) to provide continuing medical education for physicians. The ASNR designates this enduring material for a maximum of 1 AMA
PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To molecule
obtain Self-Assessment CME (SA-CME) credit for this activity, an online quiz must be successfully completed and submitted. ASNR EDAR ⫽ receptor for EDA
members may access this quiz at no charge by logging on to eCME at http://members.asnr.org. Nonmembers may pay a small fee to EDARADD ⫽ intracellular adapter
access the quiz and obtain credit via https://members.asnr.org/webcast/content/course_list.asp?srcNeurographics. Activity Release
protein EDAR-binding death
Date: October 1, 2018. Activity Termination Date: October 1, 2021.
domain adaptor
EGF ⫽ epidermal growth factor
ENAM ⫽ enamelin a protein coding
gene
ABSTRACT EPHA4 ⫽ ephrin type A receptor
The embryology of the teeth was briefly covered in a previous review in this series. This (tyrosine kinase receptor)
present review addresses this embryology in more detail. The development of the teeth is a FGF (4,8,9) ⫽ fibroblast growth
highly orchestrated, complex process that is the result of reciprocal inductions between the factor
overlying first branchial arch oral cavity ectoderm, from which the cells that produce the GAS1 ⫽ hedgehog co-receptor,
growth arrest specific-1
enamel will develop, and the neural crest ectomesenchyme, from which the remaining tooth
IL-1␣ ⫽ Interleukin-1␣ (also known as
elements will arise. Early in development, the tooth germ grows and expands, and those hematopoietin 1)
cells that will form the mineralized components of the teeth differentiate. Once these KLK4 ⫽ kallikrein-related peptidase
formative cells differentiate, formation and mineralization of the dentin and enamel matri- 4, a protein coding gene
ces occur. Eventually, the completed tooth will erupt into the oral cavity, and during erup- Laminins ⫽ high molecular proteins
of the extracellular matrix ⫽ aid in
tion, the tooth roots become surrounded by the periodontal ligament, cementum, and
anchoring the keratinocytes to
supporting alveolar bone. There is also a discussion that notes some of the various abnor- the ⫽ underlying dermis
malities that can affect the teeth. LHX6,7 ⫽ homeobox genes
MAX1/2 ⫽ homeobox genes
Learning Objective: The reader will understand the current theory as to how the human tooth
configuration arose, as well as the embryology and anatomy of the teeth, the process of tooth
eruption, alterations in the number and morphology of the teeth, and inflammatory conditions. Received October 21, 2016;
accepted February 6, 2018.
From the Department of Radiology
INTRODUCTION pacity for tooth development. This is re- (P.M.S.), Ichan School of Medicine
at Mount Sinai, New York, New
The embryology of the teeth was briefly ferred to as the “outside-in theory.” The York, and Department of
covered in a previous review in this series. 1 alternate theory, the “inside-out theory,” Craniofacial Development and
Stem Cell Biology (I.M.), King’s
Eventually, the completed tooth will erupt indicates that teeth are born from endo- College, London, United Kingdom.
into the oral cavity and during eruption, derm that originates in the posterior Please address correspondence to
the tooth roots become surrounded by the pharynx of jawless vertebrates co-opted Peter M. Som, MD, Department of
Radiology, The Mount Sinai Hospi-
periodontal ligament, cementum, and sup- anteriorly to the developing jaws during tal, One Gustave Levy Place, New
porting alveolar bone.2 Paleontologists gnathostome evolution (this period includes York, NY 10029; e-mail:
Peter.Som@MSSM.edu.
and evolutionary biologists have proposed most of the Middle Devonian period, from http://dx.doi.org/10.3174/ng.1600049
2 primary theories as to how vertebrate 380 million years ago to the present).
Disclosures
teeth evolved. The traditional theory indi- Gnathostomes have jaws and teeth, and Based on information received
cates that skin ectodermal denticles, as today’s gnathostomes include among from the authors, Neurographics
has determined that there are no
found in sharks, migrated and integrated others, sharks, rays, chimaeras, and land Financial Disclosures or Conflicts of
into the mouth to provide the inductive ca- vertebrates (Fig 1). Interest to report.

Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org 兩 369


MCP-1 ⫽ monocyte chemotactic
protein
MMP (20) ⫽ matrix
metalloproteinase
MSX1, 2 ⫽ homeobox mshlike 1 and 2
NFkB ⫽ nuclear transcription factor
NGF-R ⫽ nerve growth factor
receptor
OCP ⫽ octacalcium phosphate
OHAP ⫽ hydroxyapatite
p21 ⫽ cyclin-dependent kinase
inhibitor or cyclin-dependent-
kinase interacting protein
PAX (9) ⫽ paired box transcription
factor homeobox gene
PITX2 ⫽ homeobox gene
PTHRP ⫽ parathyroid hormone–
related protein
RUNT ⫽ RUNX ⫽ hedgehog co-
receptor, runt-related
transcription factor
RUNX2 ⫽ runt-related co-factor
involved in osteoblastic and
skeletal morphogenesis
SHH ⫽ sonic hedgehog protein
SPROUTY2 ⫽ growth
factor-antagonist
TGF (␣, ␤) ⫽ transforming growth
factor
TNF ⫽ tumor necrosis factor
WNT (10A and B) ⫽ wingless/int1
family of secreted signaling
molecules
370 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
A more current theory
proposes that odontodes
evolved as the gene regula-
tory networks of basic epi-
thelial (ectoderm or endo-
derm) structures combined
with those of migrated
neural crest cells (ectomes-
enchyme).3,4 Simply put,
odontodes developed “in-
side and out,” wherever
and whenever these co-ex-
pressed gene sets signaled to
one another. It seems that
teeth and dermal denticles
developed from the same
developmental module and
under the control of the
same set of DIX genes. In
this respect, teeth and der-
mal denticles should be con-
sidered as serial homologs
that develop through the ini- Fig 1. Origins of teeth. A, The top drawing is a stylized rendition of a
tiation of a common gene Loganellia pharyngeal denticle array (modified from Bigelow HB, Schr-
regulatory network. Other oeder WC. Sharks. In: Tee-Van J, Breder CM, Hildebrand SF, et al, eds.
genes likely included in our Fishes of the Western North Atlantic, Part 1: Lancelets, Cyclostomes,
ancestral gene regulatory Sharks. New Haven, CT: Sears Foundation for Marine Research, Yale Uni-
versity; 1948:59 –576). B, The lower drawing is of shark dermal denticles;
network are sonic hedgehog stylized drawings in the lateral view of the jaws of 2 animals; on the left
protein (SHH), ephrin type side, the teeth are conical and vertically identical; this is referred to as
A receptor (tyrosine kinase homodonty, and this was the initial form of tooth morphology; on the
receptor) (EPHA4), and right side, the teeth have varied morphology, and this is referred to as
hedgehog co-receptor, runt- heterodonty; this is the form of tooth morphology that has developed in
mammals (modified from Smith MM, Coates MI. Evolutionary origins of
related transcription factor the vertebrate dentition: phylogenetic patterns and developmental evo-
(RUNX).4 It does seem that lution. Eur J Oral Sci 1998;106(suppl 1):482–500).
teeth and toothlike struc-
tures evolved in vertebrates
became associated with bone. Initially, all of the teeth were
before and independently of
identically conical separate dental units (homodonty). The
jaw development. Thus, it
divergent morphology of teeth in the dentition (het-
seems that odontodes had
erodonty) has evolved from homodonty in a number of
their origins in ancient jaw-
species, especially in mammals (Fig 1). Teeth are vertebrate-
less agnathan vertebrates.
specific and within vertebrates, species-specific. The shape
However, the question re- of each tooth varies with its position in the jaws, and it is
mains “Did the first odon- bilaterally symmetric. It is clear that the teeth and jaws
tode appear within the evolve together, and, in hominids, the jaws are continually
evolving oropharyngeal cav- becoming smaller. Thus, the number of teeth seems to be
ity needed for food break- decreasing, and it is postulated that, in the future, human
down during the transition teeth will be composed of 1 incisor, 1 canine, 1 premolar,
to a more predatory behav- and 2 molars per quadrant.3,4
ior, or did the first toothlike
structures appear as external AN OVERVIEW OF MOLECULAR TOOTH SIGHTING
dermal armor in a predator- The cranial neural crest is a multipotent progenitor popu-
rich environment?” lation of cells that generate a wide range of derivatives.
No matter which theory These derivatives can be grouped into 2 categories: ecto-
is correct, it is apparent mesenchymal cells and nonectomesenchymal cells. The ec-
that the “teeth” migrated tomesenchymal derivatives migrate into the developing first
into the mouth, where they pharyngeal arches and facial prominences, and will form
bone, cartilage, connective tissue, and dentine. The nonec-
tomesenchymal derivatives will form neurons, glia, and pig-
ment cells, and they lie close to the neural tube, being
segregated from the ectomesenchymal cells.5 Under the in-
fluence of fibroblast growth factor (FGF) signaling, as the
neural crest cells enter the pharyngeal arches, they stop
expressing early neural crest markers and switch to become
the ectomesenchyme. By contrast, those neural crest cells
that do not enter the arches persist in their expression of
early neural crest marker.5,6
Butler,7 in 1939, postulated a regional field theory that
suggested that morphogenetic fields accounted for the way
in which the teeth within a particular class (incisor, canine,
premolar, and molar) are formed, with each tooth display-
ing similarities to adjacent teeth due to the influence of a
common field but with graded differences because of tooth
positioning. That is, these signals would have a graded con-
centration along the developing jaw axis, such that each
tooth primordium developed differently according to its
position relative to the source of the signal intensity (Fig 2).7
Osborn, in 1978, proposed a clone theory that indicated
that a single clone of preprogrammed ectomesenchymal
cells led to the development of all the teeth within a partic-
ular class. As the ectomesenchyme entered the jaws, and,
after its interaction with the oral epithelium, a clone of cells
was established for a specific tooth class. He indicated that,
as the clone of cells grew distally, tooth buds were formed
and they were surrounded by zones of inhibition that pre-
vented other teeth from developing until the migrating
clone had moved sufficiently.8 That is, activators induced
placodal formation while negative regulators, which were
highly concentrated in the interplacodal regions, prevented
tooth formation.8 This theory proposed that the shape of
the tooth was determined from the moment that its primor-
dium was initiated (Fig 2).
More recently, it was proposed that there is a homeobox
code with intermixing of the homeobox genes that are ex-
pressed by the ectomesenchyme of the first branchial arch.
These gene expressions can lead to the establishment of
different morphogenetic fields. It is thought that signals
from the ectoderm establish patterns that induce specific
domains of homeobox gene expression in the ectomesen-
chyme. This patterning is initially plastic but becomes fixed
into the “memory” of the ectomesenchymal cells. These
specific domains are postulated to provide the molecular
information needed to specify different tooth shapes.8
There are several homeobox genes that show restricted ex-
pression in the ectomesenchyme of the first branchial arch
before any morphologic signs of tooth development.
These genes include the following: homeobox mshlike 1
and 2 (MSX1/2), distal-less homeobox gene 2 (DLX1– 6),
and barH-like homeobox gene (BARX1). Although ex-
pressed in broader territories than where the teeth will de-
velop, their expression domains have been proposed to
define the competency territories that govern dental pat-
terning along the proximodistal axis. The odontogenic code
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
box model proposes that specific combinations of homeo-
box gene expressions in the future tooth ectomesenchyme
lead to the different types of teeth. The multicuspid molar
teeth are proximal, whereas the monocuspid canine and
incisor teeth are distal.9,10 Another hypothesis suggests
that each dental placode can give rise to an entire tooth
family. In this scenario, only the first tooth family buds
directly from the placode, whereas the other teeth form in
succession from the primed odontogenic epithelium and
ectomesenchyme.11,12
In addition to the homeobox code, the expression of the
ectodysplasin signaling molecule (EDA) is important in de-
fining the size of the dental fields. When EDA, EDA receptor
(EDAR), or the intracellular adaptor protein EDAR-bind-
ing death domain adaptor (EDARADD) are disrupted,
tooth abnormalities occur. Thus, in mice, overproduction
of the EDA ligand or, if the receptors for EDA are overex-
pressed, the size of the molecular field increases, which re-
sults in the formation of supernumerary teeth.8
The FGF-antagonist SPROUTY2, the hedgehog co-re-
ceptor growth arrest specific-1 (GAS1), and the RUNT-
related co-factor RUNX2 are all expressed during early
human tooth development. The domains of GAS1 and
RUNX2 are consistent with a role that influences function
of the primary dental lamina, but only GAS1 transcripts are
present in the successional lamina at the early stages of
development.13
Although, in the mouse, the dentition is less complex
than in humans (no canine or premolar teeth), it has been
shown that FGF8 and FGF9 are expressed proximally,
overlying the presumptive molar field and bone morpho-
genic protein (BMP4) is expressed distally overlying the
presumptive incisor field. These are established early in de-
velopment, before the formation of the face. These signaling
molecules then control the expression of homeobox genes
in the underlying neural crest– derived ectomesenchyme.
FGF8 and FGF9 positively regulate the expression of
BARX1 and DLX2, whereas BMP4 positively regulates the
expression of MSX1 and MSX2, and, at the same time,
negatively regulates the expression of BARX1. This results
in the restriction of BARX1 and DLX2 to the presumptive
molar region and of MSX1 and MSX2 to the presumptive
incisor region. It seems that these homeobox codes likely
are duplicated in humans.14
AN OVERVIEW OF MOLECULAR TOOTH
DEVELOPMENT
During tooth development, there are paracrine signaling
molecules of several conserved families that mediate cell
communications mainly between the ectoderm and ecto-
mesenchyme. The oral epithelium initiates tooth develop-
ment by signaling to the underlying ectomesenchyme, pri-
marily with members of the transforming growth factor ␤
(TGF-␤), FGF, SHH, and wingless/int1 family of secreted
signaling molecules (WNT). In addition, as noted, ectodys-
plasin, a signaling molecule in the tumor necrosis factor
兩 371
Fig 2. Theories of tooth development and early tooth development. A, Diagrams illustrate the regional and clone theories of tooth development.
The regional field theory suggests that identical tooth primordia (black dots) are acted on by a morphogenetic substance that has a graded
concentration in the field. This results in each tooth primordium, developing into a specific tooth with a different morphology. The clone theory
suggests that the gradient of the final tooth form is related to the times at which the tooth primordia (black dots) are initiated. The stippled
regions represent the growing margin of the clone, with an associated zone of inhibition (blue circle). The red dot represents tissues that have
reached the critical stage to form a new primordium (modified with permission from Cobourne MT, Sharpe PT. Chapter 3: tooth development.
Pocket Dentistry Web site. https://pocketdentistry.com/3-tooth-development. Fig 3.9). B, Drawings of the developing lower-lip region show
the initial development of the labiogingival lamina and its progressive desorption, which creates the labiogingival sulcus that separates the
future lower lip from the future gingiva; next, the dental lamina appears in the future gingiva; from the dental lamina, the dental placodes of the
deciduous and permanent teeth will arise.

(TNF) family, and its receptor, EDAR, mediate signaling A characteristic feature of tooth development is the reit-
between the ectodermal compartments in the developing erated and sequential appearance of transient signaling cen-
tooth. ters in the epithelium during key morphogenetic steps. The

372 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org

first signaling centers appear in the dental placodes when
epithelial budding initiates. Next during the transition from
the bud stage to the cap stage, the enamel knot signaling
centers appear, one for each future cusp of the tooth. These
enamel knots regulate the advancing morphogenesis of the
tooth crown and control the initiation of the secondary
enamel knots at the sites of the future epithelial cusp
formations.11,12
The first epithelial signals induce the ectomesenchyme to
express reciprocal signaling molecules that include activin,
FGF, and BMP4, which act back on the epithelium and
regulate the formation of the dental placode. In addition,
WNTs and ectodysplasin, secreted by the ectodermal cells,
participate in regulating dental placode development. The
placodal signals then regulate budding of the epithelium
and condensation of the ectomesenchymal cells. They main-
tain the expression of earlier induced transcription factors
in the ectomesenchyme and induce the expression of new
genes that regulate epithelial morphogenesis from the bud
stage to the cap stage.
Next, ectomesenchymal BMP4 is needed for the forma-
tion of the enamel knot at the tip of the dental bud. It
induces the expression of cyclin-dependent kinase inhibitor
(p21), which is associated with the exit of the knot cells
from the cell cycle. In addition, the EDAR receptor is also
induced in the enamel knot, which allows the cells to be-
come responsive to the ectodysplasin signaling. It is the
ectodysplasin-EDAR signaling that likely regulates the for-
mation and signaling activity of the enamel knot, and both
epithelial and ectomesenchymal cells are affected by these
signals. Subsequent reciprocal interactions between the ec-
tomesenchyme and the epithelium are responsible for the
maintenance of the enamel knot as well as for the morpho-
genesis of the epithelium. The enamel knot signals also reg-
ulate the patterning of the tooth crown by influencing the
initiation of the secondary enamel knots that determine the
sites where the epithelial sheet folds and cusp development
starts. In addition, nerve growth factor receptor (NGF-R) is
necessary for morphologic and cyto-differentiation in the
tooth, and parathyroid hormone is necessary for normal
tooth eruption.11,12,15-17
Transcription factors play a critical role in tooth devel-
opment. The expression of these numerous transcription
factors often overlaps with those of the growth factors, and
there is an inductive interaction between these 2 classes of
gene products. The primary homeobox genes include paired
box transcription factor homeobox 9 gene (PAX9), MSX1,
MSX2, DLX3, DLX5, DLX6, DLX7, BARX1, PITX2,
LHX6, and LHX7. It is suggested that there is a homeobox
code for tooth patterning and formation and that the over-
lapping expression domains of these homeobox genes may
subdivide the jaws into different regions for specifying each
tooth’s position.9,18 Results of studies have indicated that
there is tight control between these networks of activators
and inhibitors, and that any modification of these networks
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
leads to abnormalities either in the number or the pattern of
the teeth.19
In summary, during tooth development, the cells and
tissues communicate via conserved signal intensity mole-
cules that are used reiteratively during the advancing mor-
phogenesis. In addition, the variation in cellular responses
to the same signals in different tissues and at different times
is caused by the different cell histories that determine their
competence to receive and respond to the signals.11 The
early migration of neural crest cells may be primarily under
the influence of WNT and FGF8 from the epithelium. This
migration induces the ectomesenchyme to establish the den-
tal lamina, whereas PAX9 expression in the ectomesen-
chyme initiates the tooth bud. Induction of the enamel knot
by BMP4 produced by the ectomesenchyme occurs late in
the bud stage. The primary enamel knot then induces cusp
formation, primarily through the signaling molecules of
SHH, BMP2, BMP7, and FGF4. The shape of the tooth is
determined by the ectomesenchyme, and the secondary
enamel knots produce the same signaling as the primary
enamel knot. The extracellular matrix is also required for
the facilitation of epithelial-mesenchymal signaling and the
stabilization of the dental morphology.2
The Beginning
Up until the late sixth embryonic week, the primordial jaws
are composed only of masses of mesenchymal tissue, with
no differentiation between the lips and the gingivae. Near
the end of the sixth week, neural crest cells migrate into the
upper and lower jaws, which causes the overlying ectoderm
to thicken and form the curvilinear labiogingival lamina
that grows into the underlying ectomesenchyme. Eventu-
ally, most of this labiogingival lamina degenerates, which
creates a labiogingival groove or sulcus between the lips and
gingivae (Fig 2). Occasionally, a small midline remnant of
the labiogingival lamina may persist as the frenulum of the
upper lip.1,20-22
Formation of the Tooth Crown
Shortly after the sixth week, a second lamina, the dental
lamina, arises in the more medial or buccal margin of the
developing gingiva of both jaws (Fig 2). At certain prede-
termined intervals along the course of the dental lamina, the
dental placodes are induced. Not all of the dental placodes
appear at the same time. Their signaling will promote the
development of the future tooth (Fig 2B).11,12 The dental
placodes consist of thickened epithelium and underlying
neural crest– derived ectomesenchyme (Fig 3). The dental
placodes eventually give rise to 10 spherical tooth buds that
penetrate into the ectomesenchyme of both jaws (Figs 3
and 4).
Each of these tooth buds is attached to the dental lamina
by a lateral lamina, and each bud will give rise to a decidu-
ous tooth (Fig 5). The epithelial component of each dental
bud is the enamel organ. The tooth buds first appear in the
anterior mandible, followed by the anterior maxilla. Bud-
兩 373
Fig 3. The overall progression from the development of the dental placode through tooth eruption. The drawings illustrate the components of the
enamel organ, the development of the odontoblasts and dentin, and the appearance of the ameloblasts and enamel (modified from Pansky B. Review
of Medical Embryology. New York, NY: MacMillan; 1982).
Fig 4. Drawing of the developing lower right lip as seen from behind
shows the labiogingival sulcus and the dental lamina. Note the deciduous
tooth buds successionally developing from the dental lamina (modified
with permission from Avery JK, Steele PF, eds. Oral Development and
Histology. 3rd ed. Stuttgart, Germany: Thieme; 1994. Fig 5.5, p 74).
ding then continues progressively posteriorly in both the
maxilla and mandible. After the 10th fetal month, deep
components of the dental lamina create the buds for the
permanent teeth along the lingual aspects of the deciduous
teeth. The permanent molar teeth that have no deciduous
precursors arise directly from posterior extensions of the
dental laminae.1,20-22 As each tooth germ continues to de-
velop, it eventually loses its connection with the dental
lamina. Mesenchymal invasion then starts to break up the
dental lamina, which is, at first, incomplete (Fig 5). Frag-
374 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
mentation of the dental lamina then progresses toward the
developing enamel organ.
Continued Tooth Development
By the 10th week, induction from the ectoderm causes the
ectomesenchyme below the tooth bud to further condense
and the ectodermal tooth bud extends partly around these
condensed cells and creates a cap-shaped dental organ, re-
ferred to as the cap stage of development (Fig 3). The ecto-
mesenchymal tissue is the dental papilla, and it will give rise
to most of the tooth proper, including the pulp cavity, the
dentin, and the vasculature of the tooth. The upper portion,
or enamel organ, has an inner enamel epithelium (the
ameloblastic layer), an outer enamel epithelium, and an
intervening stellate reticulum (the enamel pulp), and the
stratum intermedium (Fig 6).9,11,18
The stratum intermedium, whose cells may help orches-
trate the progression of odontogenesis, is a transient epithe-
lial structure that lies against the inner enamel epithelium,
and it is attached by desmosomes to the basal or proximal
end of these cells, which will become preameloblasts. The
apical ends of the preameloblasts are attached to a base-
ment membrane (the basal lamina) by hemidesmosomes,
and this latter attachment will be the site of the future
dentinoenamel junction (Fig 7). The cells of the stratum
Fig 5. Drawings of the dental lamina and the lateral lamina, from which the dental enamel organ arises. A, The dental lamina is intact. B, The dental
lamina has started to degenerate, which leaves the developing tooth unattached from the oral epithelium; eventually, the tooth germ will lie within a
bony crypt created by the dental follicle (modified with permission from Avery JK, Steele PF, eds. Oral Development and Histology. 3rd ed. Stuttgart,
Germany: Thieme; 1994. Fig 5.11, p 77).
Fig 6. Schematic drawing of the enamel organ, showing its various cel-
lular components and their relationship to one another.
intermedium have high alkaline phosphatase activity, and
they assist the inner enamel epithelium– derived amelo-
blasts to form enamel.23
The cells of the stellate reticulum are sandwiched be-
tween the outer enamel epithelium and the stratum inter-
medium. These stellate cells secrete hydrophilic glycosami-
noglycans into the extracellular compartment, and this
causes water to diffuse into the enamel organ, which forces
the cells apart. As the cells are interconnected by desmo-
somes, they become stretched into a star shape and thus are
referred to as the stellate reticulum.23 Overall, they have a
cushionlike consistency that may support and protect the
delicate enamel organ.9,11,18
The enamel organ and the dental papilla are surrounded
by a mesenchymal condensation referred to as the dental
follicle, or the dental sac. This follicle will eventually create
a bony crypt around the developing tooth germ (Fig 7). The
outer cells of the dental sac will eventually develop into the
cementum as well as the fibrous connective tissue that is
the periodontal ligament that attaches the tooth roots to the
alveolar bone. Thus, at this stage, the tooth or dental organ
has 3 distinct parts; the enamel organ, the dental papilla,
and the dental follicle or sac. At all stages of tooth develop-
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
ment, the tooth is protected and stabilized by this dental
follicle.1,20-22
By the third month, the ectomesenchymal cells in the
dental papilla adjacent to the inner enamel epithelium have
differentiated into odontoblasts. It seems that contact with
the basal lamina and its associated matrix is the trigger for
odontoblastic differentiation. This represents an example
of a short-range matrix-mediated interaction. Late in their
differentiation, the odontoblasts withdraw from the cell
cycle, elongate, and start secreting predentin from their api-
cal surfaces. This process of dentin formation, or dentino-
genesis, signals a shift from the synthesis of type III collagen
and fibronectin to type I collagen and other molecules, for
example, dentin phosphoprotein and dentin osteocalcin,
that characterize the dentin matrix. This nonmineralized
predentin is deposited adjacent to the inner enamel epithe-
lium and the production of the predentin is induced by
signals from the inner enamel epithelium, a process that
begins at the apex of the tooth. The tooth primordium now
acquires a bell shape, and it is referred to as the bell stage
(Fig 3).2
In the sixth month, the predentin calcifies to become the
dentin of the tooth. As the dentin thickens, the odontoblasts
regress toward the center of the dental papilla, and some
odontoblastic processes remain embedded in the dentin.
These processes (also called Tomes processes) cause the
secretion of hydroxyapatite (OHAP) crystals and the even-
tual mineralization of the matrix. This type of dentin forms
from a pre-existing ground substance in the dental papilla
and is located beneath the enamel and under the dentinoe-
namel junction. It is referred to as mantle dentin.24
Other odontoblasts enlarge and form predentin that then
undergoes mineralization. This results in a tightly ar-
ranged dentin, and it is referred to as primary dentin.
Secondary dentin occurs at a slower rate than mantle and
primary dentin. It is formed after root formation is com-
pleted and starts at the cervical loop area, where the
outer and inner enamel epithelial layers join together. It
then proceeds toward the root. This process continues
throughout life and is responsible for the smaller pulp
found in the teeth of older people.24 Tertiary dentin, or
兩 375
Fig 7. A, Schematic drawing of a developing tooth in the early bell stage, with the beginning production of dentin; the various cell layers are illustrated.
B, The drawing in a later bell stage as the ameloblasts have developed; the various cell layers are again shown, as well as the dental follicle that will
produce the bony crypt that encases the developing tooth.

reparative dentin, forms in reaction to a stimulus, such as
dental caries (Fig 8). Most of the cells in the developing
dental pulp are fibroblasts in a delicate reticulum. There are
a few larger blood vessels present in the central pulp, and
smaller vessels are present in the periphery. There are only a
few small nerves associated with the blood vessels that enter
the young pulp. It is only later, as the teeth erupt, that larger
myelinated nerves become abundant throughout the pulp.2
The predentin is formed along the dental pulp border in
daily increments. The more peripheral adjacent predentin
that was formed the previous day then mineralizes and be-
comes dentin. As the predentin calcifies and becomes den-
tin, the mineralization front or the predentin-dentin junc-
tion is established. During formation of the crown and after
tooth eruption, the predentin is continuously formed along
the pulpal border and then calcified along the predentin-
dentin junction. It is during this time that the dental papilla
becomes the dental pulp, and, as a result of the daily incre-
mental growth of the dentin, there is a gradual decrease in
the volume of the dental pulp. Incremental lines are present
within the dentin and are believed to be due to hesitation in
matrix formation and subsequent altered mineralization.2

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Fig 8. Schematic drawing of a tooth illustrates the locations of the vari-
ous types of dentin within the tooth.
Enamel formation occurs after dentin formation in the
late bell stage of tooth development. The formation of the
enamel, or amelogenesis, occurs in several stages: a pres-
ecretory, secretory, transitional, and maturation stage.
Soon after the deposition of the first layer of predentin
(mantle dentin), the adjacent inner enamel epithelial cells
express matrix metalloproteinases (MMP) that digest the
epithelial basement membrane. This allows these cells to
differentiate into preameloblasts, and they can now contact
the newly formed predentin. This induces the preamelo-
blasts to differentiate into ameloblasts and start the depo-
sition of the enamel matrix. A strong mechanical bond is
formed between the enamel and the dentin, and this estab-
lishes the dentinoenamel junction. As the ameloblasts dif-
ferentiate, they elongate and their nuclei shift away from the
pulp cavity. The cytoplasm becomes filled with organelles
needed for synthesis and secretion of the enamel proteins.
The ameloblast starts to synthesize and secrete enamel pro-
teins in the form of prisms and rods against the newly min-
eralized mantle dentin, and fine OHAP crystals become
packed perpendicular to the ameloblasts flat proximal ends.
Presecretory ameloblasts send out small processes
through the degenerating basement membrane as they ini-
tiate the secretion of enamel proteins on the surface of min-
eralizing dentin. After establishing the dentinoenamel junc-
tion and mineralizing a thin layer of aprismatic or rodless
enamel, the ameloblasts migrate away from the dentin sur-
face. As they start to migrate, they form a conical projection
or specialized secretory process called a Tomes process (Fig
9). Along the secretory side of the Tomes process, in place of
the absent basement membrane, the secretory ameloblasts
secrete large amounts of enamel matrix proteins so that the
nascent enamel layer can thicken. Each ameloblast will
form a rod or prism, and, collectively, these prisms will
form a highly organized 3-dimensional structure. That is, as
the enamel layer thickens, the ameloblasts move away from
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
the dentin. At the end of the secretory phase, the amelo-
blasts lose their Tomes processes and produce a thin layer of
aprismatic enamel. At this point, the enamel has achieved its
final thickness. During the transition stage, the ameloblasts
undergo a major restructuring that diminishes their secre-
tory activity and changes the types of proteins they secrete.
During the maturation phase, the ameloblasts harden the
enamel layer, and, once enamel formation has been initi-
ated, these proteins are degraded into smaller fractions, and
they are gradually removed from the matrix by altered
ameloblasts, the same ameloblasts that earlier transported
these proteins for the formation of the enamel. By removing
these proteins out of the enamel, new space is provided for
new enamel crystals to grow. Finally, the enamel is com-
pletely mineralized.25 Thus, ameloblasts first form an incre-
ment of organic matrix, which later mineralizes. As daily
increments of organic matrix form, the adjacent earlier
formed increment mineralizes. The striae of Retzius are
lines within the enamel that mark the successive increment
enamel fronts. Both enamel and dentin form by incremental
deposition (Fig 10).
The earliest crystallites of enamel appear as rapidly
growing ribbons at the dentinoenamel junction. The shape
and growth patterns of the crystallites indicate that there is
a precursor phase of octacalcium phosphate (OCP), which
may act as a template for OHAP precipitation. The OCP is
less stable than OHAP and can hydrolyze to OHAP, and,
during this process, 1 unit of OCP is converted into 2 units
of OHAP. The actual mineralization is partially under the
influence of the enzyme alkaline phosphatase. Crystal for-
mation initially takes place in a gel-like matrix, composed
of spherical aggregates of amelogenin molecules, a major
component of the enamel matrix. Amelogenin then regu-
lates crystal formation by interacting with enamelin, a mi-
nor matrix protein, and inorganic fluid components. Other
proteins involved in the process include ameloblastins and
tuftelins.25 Enamel is composed of OHAP crystals that re-
sult in enamel being formed of 96% mineral and 4% or-
ganic material and water.1,20-22,26,27
The tooth crown, that portion of the tooth that is cov-
ered by enamel and that projects above the gum, is formed
by both the dentin and enamel. The formation of the crown
starts at the tooth cusp and progresses downward toward
the roots. As the amount of dentin increases, the pulp cavity
gets smaller and eventually will become a narrow canal for
the vessels and nerves that enter the tooth root.1,20-22
Under the influence of the dental papilla, a small group of
ectodermal cells at the tip of the dental papilla cease divid-
ing. These cells form the enamel knot, a signaling center
that regulates the shape of the developing tooth. The enamel
knot stimulates the proliferation of cells in the dental cap
and determines the site of the tip of the cusp in the devel-
oping tooth. In the molar teeth that have multiple cusps,
there are secondary enamel knots, one for each cusp. Ulti-
mately, the cells of the enamel knot undergo apoptosis.12
兩 377
Fig 9. Drawings of enamel formation. A, An ameloblast before and after the development of a Tomes process is shown. B, The drawing shows a
3-dimensional representation of enamel and the orientation of the enamel rods. C, The drawing illustrates the enamel crystallites arising from the
Tomes ameloblast. D, The drawing shows the difference between aprismatic and prismatic enamel.

secrete enamel matrix proteins at the developing dentinoe-

Fig 10. Idealized drawing of a tooth illustrates the incremental growth
lines within the enamel (stria of Retzius) and within the dentin (lines of
von Ebner). Also shown is the pulp and its vessels and nerves, as well as
an accessory root canal.
The primary knot appears in the cap stage, whereas any
secondary knots appear in the bell stage.
In summary, enamel development can be described in 4
stages. During the presecretory stage, the ameloblasts pen-
etrate and then remove the basal lamina. They then start to
namel junction. Soon the ameloblasts enter the secretory
stage, during which they elongate, develop Tomes pro-
cesses, and secrete large amounts of proteins into the
enamel matrix. These proteins are necessary so that the
enamel crystallite ribbons can form and then lengthen.
Once the enamel reaches its full thickness, the ameloblasts
enter the maturation stage, in which they transition into
shorter protein-reabsorbing cells. At the end of this stage,
the enamel has achieved its final hardened form.27 The
enamel mineralization follows the pattern of matrix forma-
tion that originates from the dentinoenamel junction.
As the permanent teeth are developing, the original epi-
thelial strand that connects the dental primordium with the
oral cavity is called the gubernaculum dentis. As the alveo-
lar bone forms around the developing teeth, it spares the
gubernaculum dentis, and this produces a gubernacular ca-
nal between the crypt of the developing tooth germ and the
oral cavity. This canal is primarily found in association with
the incisor and canine teeth, along the lingual alveolus (Fig
11). These canals seem to aid the eruption path for the
permanent teeth.28 By the late bell stage, the dental lamina
and lateral dental lamina have degenerated, and the devel-
oping tooth is independent of the oral mucosa.

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Fig 11. Drawing of the palate and deciduous maxillary teeth as seen from
below. The green arrows point to the gubernacular canals that act as a
pathway for the permanent teeth to erupt (modified with permission
from Putz R, Pabst R, eds. Sobotta Atlas of Human Anatomy Volume 1:
Head, Neck, Upper Limb. 13th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2000. Fig 187, p 105).
Fig 12. Drawing of a tooth in the bell stage. The crown is nearly com-
pleted, and the outer (ameloblast layer) and inner (odontoblast layer) of
the original outer and inner enamel epithelial layers have joined at the
level of the cervical loop to form the Hertwig epithelial root sheath that
will form the tooth root. Eventually, the root sheath bends inward to form
the epithelial diaphragm that will form the root canal(s) (modified with
permission from Cobourne MT, Sharpe PT. Chapter 21: Root formation and
attachment apparatus. Pocket Dentistry Web site. https://pocketdentistry.
com/21-root-formation-and-attachment-apparatus. Fig 21.1).

FORMATION OF THE TOOTH ROOT

Tooth root formation begins after the formation of the
crown is nearly complete, but before calcification of the full
crown. This occurs in the late fetal and early postnatal
period. The formation of the tooth root begins under the
guidance of the double-layered epithelial sheath that forms
when the inner and outer enamel epithelial layers come
together without an intervening stellate region. These
joined layers form the epithelial root sheath (or Hertwig
epithelial root sheath) in the region of the tooth neck (at the
base of the crown) (Fig 12). Specifically, the outer enamel
epithelium and the inner enamel epithelium join at what is
referred to as the cervical loop, a continuous irregular line
that marks the end of the tooth crown and the cementoe-
namel junction located at the neck of the tooth root, where
the cementum meets the enamel (Fig 13). The root sheath
begins to undergo rapid mitotic division and then grows
deeply into the underlying connective tissue, signaling the
Fig 13. Drawing of a tooth illustrates the location of the cervical loop that
beginning of the tooth root formation. Primarily by secret- marks the cementoenamel junction (modified with permission from Co-
ing laminin 5 and TGF-␤, the root sheath is critical for the bourne MT, Sharpe PT. Pocket Dentistry Web site. https://pocketdentistry.
development of the root dentin, the root cementum, and the com/).
number of tooth roots.1,20-22
The dental papilla is on the inner side, and the dental sac forming the root length, the epithelial diaphragm continues to
is on the outer side of the developing root. As the apical grow inward. If the entire circumference of the diaphragm
growth continues, the tip of the epithelial root sheath turns grows inward evenly, then a single root is formed. If 2 opposite
horizontally inward and forms the epithelial diaphragm of sides of the epithelial diaphragm grow inward more rapidly
the root sheath (Fig 12). The epithelial root sheath and the and eventually meet in the center of the diaphragm, then 2
epithelial diaphragm will guide the shape and the number of roots will be formed. If 3 areas grow inward to meet, then
roots. The manner in which the epithelial diaphragm goes there will be 3 roots (Fig 14).
inward determines whether the tooth will have 1, 2, or 3 roots. As the root sheath grows from the cervical line deeper into
If there is incomplete fusion of the tonguelike extensions of the the connective tissue, it influences the peripheral cells of the
epithelial diaphragm, then an accessory root canal will de- dental pulp to change into odontoblasts, in a similar manner to
velop. As the vertical epithelial root sheath grows longer, what happens in the crown of the tooth. The odontoblasts

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Fig 14. Drawings illustrate how the closure of the epithelial diaphragm
can form single, double, or triple root canals.
begin to secrete a matrix that then calcifies to form the dentin
of the developing root. Once the dentin begins to form next to
the root sheath, the root sheath begins to degenerate. It is
unclear as to whether this breaking up of the root sheath is
caused by the odontoblasts on the inner side or the cells in the
dental sac on the outside (Fig 15).1,20-22
More specifically, the epithelial root sheath is initially a
solid wall of cells surrounding the developing tooth root. As
it starts to break up, gaps appear in it, which allows the
odontoblasts and dentin on the inside of the root to contact
the dental sac on the outside. As the undifferentiated ecto-
mesenchymal cells of the dental sac come into contact with
the newly formed dentin surface, they become differentiated
into cementoblasts that form cementum. The cementum is laid
down against the previously formed dentin, and this estab-
lishes the dentinocemental junction of the root. As the root
sheath continues to degenerate and pull away from the dentin,
the dentinocemental junction is able to extend over the entire
tooth root. Occasionally, some of the epithelial root sheath
cells do not pull away from the tooth root and they form
ameloblasts that then form small areas of enamel on the sur-
face of the dentin. These are called enamel pearls.
After the cells of the epithelial root sheath have broken
up and moved away from the dentin, any remaining root
sheath cells will be located in the periodontal space, next to
the tooth, and these are called epithelial rests of Malassez
(Fig 15). As increasing amounts of dentin develop, they
reduce the pulp cavity to the narrow root canal through
which the vessel and the nerves pass. Although the structure
and composition of dentin in the crown and root are simi-
380 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
lar, their development is different, with the mature odonto-
blasts in the crown being elongated, irregular columnar
shaped, whereas the odontoblasts in the root are cuboidal
in shape.1,20-22,26,27
The cementum occurs in 2 basic forms: cellular and acel-
lular. Acellular (or primary) cementum occurs first when
the cementoblasts differentiate from dental sac cells. These
cells can reach the tooth surface once the root sheath has
started to deteriorate. The cementoblasts secrete fine colla-
gen fibrils at right angles along the root surface. As the
cementoblasts move away from the tooth root, more colla-
gen is deposited, and this lengthens and thickens the fibers.
Proteins such as sialoprotein and osteocalcin are also se-
creted by the cementoblasts. Acellular cementum has a se-
creted matrix of proteins and fibers. As mineralization oc-
curs, the cementoblasts move away from the cementum and
the fibers left along the surface eventually join the forming
periodontal ligaments. Thus, acellular cementum forms
during root formation and is present over the tooth roots. It
contains no cells, and its arrangement of collagen fibers is
more organized then that of cellular cementum (Fig 16).27
Cellular cementum occurs after tooth formation is com-
plete and after the tooth has contacted a neighboring tooth
or a tooth in the opposite arch. This cementum forms
around bundles of the periodontal ligament, and the cemen-
toblasts become trapped in the cementum that they pro-
duce. These cementoblasts are believed to develop from the
adjacent bone, and this type of cellular cementum only oc-
curs in those teeth that have multiple roots. In summary,
cellular cementum forms after the eruption of the tooth and
is present on the root apices. It contains cementocytes, and
its deposition is more rapid than that of acellular cemen-
tum. Formation of cementum is a continuous process, the
rate of which varies throughout life. It is most rapid at the
root apices. At the cementoenamel junction, in nearly 60%
of people, the cementum overlaps the enamel. In 30% of
people, the cementum just meets the enamel, and, in 5%–
10% of people, the cementum and enamel do not meet.
In summary, dentin is encased by enamel over the crown
and by cementum over the roots. The first cementum depos-
ited on the surface of the roots is called intermediate cemen-
tum and is formed by the inner epithelial root sheath cells
that formed during dentin formation. This deposition oc-
curs before the Hertwig epithelial root sheath disintegrates.
The intermediate cementum is situated between the granu-
lar dentin layer of Tomes and the secondary cementum that
is formed by the cementoblasts. These cementoblasts arise
from the dental follicle (sac).
The initial thin layer of cementum is acellular (primary
cementum) and is deposited on the intermediate cementum.
Subsequent layers alternate between cellular (secondary ce-
mentum) and acellular. Thus, cementum is deposited incre-
mentally. Unlike bone, cementum does not contain blood
vessels, nerves, or haversian or Volkmann canals, which are
the nutrient canals that contain blood vessels and nerves in
bone. With the increasing length of the tooth root, the
Fig 15. Development of the cementum and periodontal ligament. A, Serial drawing illustrates how, as the root sheath breaks down, the odontoblasts contact
the dental sac or follicle and initiate the development of the cementum and the periodontal ligament (modified with permission from Cobourne MT, Sharpe
PT. Chapter 21: Root formation and attachment apparatus. Pocket Dentistry Web site. https://pocketdentistry.com/21-root-formation-and-attachment-
apparatus. Fig 21.4). B, The process of cementum and periodontal ligament formation is shown in greater detail, as well as the location of the epithelial rests
of Malassez. C, The dentin channels are shown in a magnified view; as gum recession occurs, the dentin channels can become exposed and cause tooth pain.

Fig 16. The junction of the tooth and gum. A, Stylized drawing of the junction of the gum and the tooth crown illustrates the locations of the gingival
sulcus, the sulcular epithelium, and the junctional epithelium. B, The drawing shows the distribution of the acellular and cellular cementum.

crown starts to move away from the base of the crypt and
toward the occlusal plane. This provides space for the con-
tinued growth of the root.
THE PERIODONTIUM
The periodontium is the supporting structure of the tooth. It
attaches the tooth to the surrounding tissues and is com-
posed of the cementum, the periodontal ligaments, the al-
veolar bone, and the gingiva.
THE PERIODONTAL LIGAMENT
As the root sheath is beginning to break up, collagen
fibers secreted by the outer cells of the dental sac become
embedded into the newly formed cementum matrix and
fix the root to the alveolar bone. This is the periodontal
ligament, and it stabilizes each tooth to the alveolar
socket bone. The periodontal ligament is located between
the cementum of the root and the adjacent bony alveolus.
The early collagen fibers are short, and their arrangement

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Fig 17. Innervation and vascular supply of the neural pulp. A, Drawing illustrates that the most concentrated vessels and nerves are at the
pulp-dentin junction (modified with permission from Netter FH. Atlas of Human Anatomy. 5th ed. Philadelphia, PA: Saunders Elsevier; 2011. Plate
57). B, The drawing shows the branches of the maxillary and mandibular nerves that innervate the teeth (modified with permission from Putz R,
Pabst R, eds. Sobotta Atlas of Human Anatomy Volume 1: Head, Neck, Upper Limb. 13th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000.
Fig 189, p 106).

is disorganized. However, later, the fibroblasts, prefibro-
blasts, and stem cells in the dental sac are activated and
the fibers become thick and well organized. The peri-
odontal ligament is dynamic, being influenced by the ad-
jacent teeth and the tooth opposing it in the opposite
arch.
Osteoblasts form from the dental sac as the root and the
cementum are forming. This bone, which surrounds the
tooth root, is referred to as alveolar bone and it forms
the tooth socket into which the tooth will be secured.
Throughout life, the alveolar bone goes through a dynamic
process, which consists of bone production from the osteo-
blasts and bone resorption from osteoclasts. If the root
sheath continuity is broken before dentin formation, then
the odontoblasts would not differentiate at this site and
dentin would not form opposite the defect in the root
sheath. This results in a small lateral canal that connects the
periodontal ligament with the main root canal, called an
accessory root canal, and it may develop anywhere along
the root (Fig 10).2
The dentogingival junction is the site where the gingiva
and the tooth meet. The cells of this junction derive from a
mass of epithelial cells known as the epithelial cuff. Hemi-
desmosomes develop between the gingiva and the tooth,
thus becoming the primary epithelial attachment. These
hemidesmosomes provide anchorage between cells by small
filamentlike structures that come from the remnants of the
ameloblasts. The junctional epithelium forms from reduced
enamel epithelium, a product of the enamel organ. The
rapid growth of this epithelium results in its increasing size
and the further isolation of the remnants of the ameloblasts,
which, as they degenerate, create the gingival sulcus and the
sulcular epithelium (Fig 16).29
THE NERVES AND BLOOD VESSELS
There are unmyelinated autonomic nerves that arise from
the superior sympathetic cervical ganglion and follow the
blood vessels in the tooth. These nerves innervate the
smooth muscle of the arterioles and thus function to regu-
late the blood flow to the capillary network of the pulp.
There also are myelinated fibers from the maxillary and
mandibular branches of the trigeminal nerve that primarily
sense pain (Fig 17). They terminate in the pulp, whereas
some nerves send out fibers just under the odontoblast layer
that form the subodontoblastic plexus (of Raschkow). This
plexus is primarily located in the roof and lateral walls of
the coronal pulp. From this plexus, the fibers become
unmyelinated and they extend toward the odontoblasts,
where they lose their Schwann cells. They terminate as free
nerve endings near the odontoblasts and extend between
them, functioning to transmit pain stimuli (Fig 17).30,31
The outer enamel epithelium functions to organize a net-
work of capillaries that will bring nutrients to the amelo-
blasts. Before enamel formation, which occurs at the end of
the bell stage, the initially smooth outer enamel epithelium
develops folds, in between which the ectomesenchyme of
the dental follicle forms papillae that contain capillary
loops that will provide nutritional supply to the enamel
organ.
The primary blood vessels enter the dental papilla in the
cap stage, and they reach a peak in numbers at the start of
the bell stage. These vessels enter the pulp cavity via the
apical foramen in the root as small arterioles. Once they
reach the pulp chamber, they branch out peripherally to
form an attenuated capillary plexus immediately under the
odontoblast layer. The capillaries have numerous pores,
which reflect the metabolic activity of the odontoblasts.
Then, this plexus branches and extends in between the

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Fig 18. Drawing of blood vessels of the tooth and the adjacent supporting
structures.
odontoblasts, nearly reaching the predentin. Small venules
then drain the capillary bed and eventually leave the pulp as
veins via the apical foramen. The branches of the alveolar
arteries supply both the tooth and its supporting tissues.
The periodontal vessels enter the pulp via the apical fora-
men or, occasionally, via an accessory foramen (Fig 18).30 It
is believed by some but not by all investigators, that there
are small, lymphatic vessels that enter the tooth via the
apical foramen and join venules in the central pulp region.
There are lymphatic vessels that drain the periodontal liga-
ment region.30
AN OVERVIEW OF THE DENTAL PULP
Immediately above the pulp is the dentin zone, which, al-
though adjacent to the pulp, is not part of the pulp zones.
The most peripheral region of the pulp is referred to as the
odontogenic zone. It is in this layer that the dental pulp cells
differentiate into the dentin-forming odontoblasts. Imme-
diately more central to the odontogenic zone is the cell-free
zone of Weil. In this region, there are numerous bundles of
reticular or Korff fibers, which pass from the central pulp
across the cell-free zone and then between the odontoblasts,
with their distal ends being incorporated into the matrix of
the dentin layer. There also are numerous capillaries and
nerves found in this layer. The next zone, more centrally, is
the cell-rich zone that contains numerous fibroblasts, the
predominant cell type of the pulp. The deep pulp cavity is
medial or central to the cell-rich zone, and it contains the
subodontoblastic plexus of Raschkow (Fig 19).30
ALVEOLAR BONE
The alveolar bone develops as the tooth develops, initially
creating a thin bony shell around the tooth germ, which is
termed the tooth crypt, that develops from the tooth follicle.
As the roots grow, the alveolar bone keeps pace with the
elongating and eventually erupting tooth as well as main-
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
Fig 19. Stylized drawing of the pulp-dentin complex illustrates the zones
of the pulp and the extension of the nerves and vessels into the
odontoblasts.
taining a relationship with each tooth root. In the eighth
week, the tooth germs are initially developing freely within
the groove of the dental lamina. Gradually, bony septa de-
velop between the teeth so that each tooth is eventually
contained in a separate crypt. The actual alveolar process
only develops during tooth eruption. The bone between the
roots of adjacent teeth is referred to as the interdental sep-
tum. The bone between the roots of multirooted teeth is
known as the interradicular septum or bone.2
TOOTH ERUPTION
After the formation of the crown is complete and root for-
mation has begun, an active process of eruption is initiated
that moves the developing tooth toward its functional oc-
clusal location. The first part of this process is termed the
intraosseous phase, and it consists of the tooth moving
through the alveolar bone and, for permanent teeth, the
space previously occupied by the roots of the primary teeth.
As the tooth nears mucosal penetration, the speed of the
eruption starts to accelerate. When the actual occlusal plane
is reached, the rapid phase of eruption comes to a halt and
consolidation of the periodontal support of the tooth oc-
curs, as does closure of the root apex. Later, actual tooth
eruption occurs, as does continued slow growth of the al-
veolar height. This growth of the alveolus helps maintain
the vertical dimension of the face and likely compensates for
any occlusal attrition. If contact is lost with the teeth in the
opposite arch, the alveolar growth and eruption rates in-
crease again. When root formation occurs, it is at the ex-
pense of the basal bone, and this occurs without movement
of the crown. Most of the root growth occurs during the
stage of rapid preocclusal eruption.28
The dental follicle, or dental sac, is required for tooth
eruption because it regulates alveolar bone resorption and
alveolar bone formation. Being interposed between the
alveolar bone of the tooth socket and the enamel organ of
the unerupted tooth, the follicle is ideally positioned to
regulate alveolar bone activity. It initiates and regulates
兩 383

Fig 20. Drawing of the hard palate and deciduous teeth of a child super-
imposed on the hard palate and permanent teeth of an adult. The en-
largement of the jaws is clearly shown. The space between the deciduous
teeth is also wider than the space between the permanent teeth (modi-
fied with permission from Putz R, Pabst R, eds. Sobotta Atlas of Human
Anatomy Volume 1: Head, Neck, Upper Limb. 13th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2000. Figs 187 and 188, p 105).
osteoclastogenesis and osteogenesis, at least for the in-
traosseous phase of eruption. The second phase of tooth
eruption is the supraosseous phase, and the follicle may play
a lesser role at this time. It is not until the supraosseous
phase that the dental follicle finally attaches to the alveolar
bone and cementum by becoming the periodontal ligament,
and this ligament then aids movement of the tooth to its
occlusal plane. Stem cells also occur in the periodontal lig-
ament, and they are pluripotent and capable of differenti-
ating into adipocytes, neurons, and osteoblasts. Thus, these
stem cells may also contribute to bone formation as well as
the formation of cementoblasts.32
Before the start of tooth eruption, osteoclastic precursors
are recruited into the dental follicle. These cells then become
mature osteoclasts that resorb the alveolar bone, forming
an eruption pathway for the tooth to reach the alveolar
surface. More specifically, paracrine signaling between the
stellate reticulum and the dental follicle occurs with cells in
the stellate reticulum expressing TGF-␤1, interleukin (⌱L)
1␣, and parathyroid hormone–related protein (PTHRP),
which cause monocyte chemotactic protein (MCP-1) and
colony-stimulating factor 1 (CSF-1) to develop in the dental
reticulum. These draw mononuclear cells to the dental fol-
licle and fuse and become osteoclast precursors. Finally,
osteoclasts move to the alveolar bone.17,33,34
An overview of tooth eruption shows that, in the pre-
eruptive phase, the developing tooth germs are constantly
moving within the alveolar processes of the jaws to main-
tain their normal positions in the expanding jaws (Fig 20).
Next, the prefunctional eruptive phase starts with the initi-
ation of root formation and ends when the teeth reach their
384 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
occlusal contacts. As the tooth moves toward the occlusal
plane and contacts the oral mucosa, the reduced enamel
epithelium that covers the crown contacts the oral epithe-
lium. A firm attachment with the oral epithelium then de-
velops, and this fused double epithelial layer lies over the
crown of the erupting tooth. As the tip of the crown enters
the oral cavity, this double layer is breached and the begin-
ning stage of clinical eruption starts. As the crown further
erupts, the oral mucosa bordering the tooth becomes the
dentogingival junction. The reduced enamel epithelium sur-
rounding the crown is known as the junctional or attach-
ment epithelium. When the tip of the crown appears in the
oral cavity, approximately one-half to two-thirds of the
roots are formed.2
The final posteruptive or functional phase occurs once
the tooth reaches occlusion. As the alveolar processes con-
tinue to enlarge their height, the tooth roots also continue to
grow. The surrounding bone attenuation increases, and the
periodontal ligaments are further established. After the
tooth reaches functional occlusion, the periodontal fibers
attach to the apical cementum and extend into the alveolar
bone. The periodontal ligament fibroblasts are able to pro-
vide sufficient force to move the tooth toward eruption.
The shedding of the primary or deciduous teeth is
thought to be the result of the loss of the tooth roots due to
increased osteoclastic activity. In turn, this causes a loss of
the attachments to the periodontal ligaments. In addition,
there is modification of the surrounding bone, and, as a
result of the growth and the increased strength of the mus-
cles of mastication, there is an increased masticatory force
that further works on the weakened tooth support. This
causes compression and weakening of the periodontal liga-
ment as well as promoting further resorption of both the
tooth roots and the alveolar bone.
The deciduous teeth erupt through the gingiva between 6
and 24 months after birth. The permanent teeth develop in
a similar manner to that of the deciduous teeth. As a per-
manent tooth grows, osteoclasts gradually resorb the
root(s) of the corresponding deciduous tooth, and, eventu-
ally, the deciduous tooth is shed and consists only of the
crown and the upper-most root (Fig 21). The accepted age
range for the eruption of the deciduous and permanent teeth
is shown in Figure 22.
AN OVERVIEW OF MOLECULAR TOOTH ROOT
ERUPTION
Tooth eruption is a programmed, localized event that in-
volves a given tooth erupting at its appointed time. Before
tooth eruption, mononuclear osteoblastic precursors are re-
cruited into the dental follicle. These cells, in turn, will fuse
to form osteoclasts that will resorb the alveolar bone to
form an eruption pathway for the tooth to exit its bony
crypt. Based on mice experiments, CSF-1 and MCP-1 are
needed to recruit the monocytes to the follicle (and for
molar tooth eruption). Osteoclastogenesis that is needed for
bone resorption likely involves inhibition of osteoprote-

Fig 21. An enlarged view of the drawing from Fig 3 illustrates the eruption
of a permanent tooth under a deciduous tooth. Osteoclastic activity and
pressure from the erupting permanent tooth have eroded some of the
root structure of the deciduous tooth. Almost all erupted deciduous
teeth have partial erosion of their roots (modified from Chapter 4: Oral
anatomy. Integrated Publishing Web site. http://medical.tpub.com/
14274/css/Chapter-4-Oral-Anatomy-55.htm. Fig 4 –1).
gerin transcription and synthesis within the follicle as well
as enhancement of the receptor activator nuclear transcrip-
tion factor (NFkB) ligand in the adjacent alveolar bone
and/or in the follicle. In addition, parathyroid-hormone–
related protein and IL-1␣, produced in the adjacent stellate
reticulum, also play a role in regulating tooth eruption.
There is also evidence that osteoblast-specific transcription
factor (CBFA1) (RUNX2) plays a role in the molecular
events that regulate tooth eruption. Among others, epider-
mal growth factor (EGF) and TGF-␣ are also needed to
initiate tooth eruption (primarily for incisor eruption).33
WHEN THINGS GO WRONG
There are a large number of dental abnormalities that can
occur either as isolated events or as a part of a syndrome. In
this section, a few of the more common of these abnormal-
ities are mentioned. Some of the abnormalities that can
affect individual teeth are illustrated in Figure 23.
Occasionally, a primary tooth can be retained as the
result of either the absence or impaction of its associated
permanent successor tooth. Such a retained tooth may re-
main functional alongside of the permanent teeth until the
retained tooth is finally shed, primarily due to resorption of
its roots. A submerged primary tooth may also become
ankylosed to the alveolar bone, and such a tooth should be
removed as soon as possible so as not to interfere with the
eruption of the permanent teeth. There also can be retained
root remnants of a primary tooth, usually found in the
interdental space. Rarely, there can be rootless preprimary
teeth present at birth. If not shed in the first few weeks of
life, then they should be removed.2
There are genetic anomalies associated only with the
number of teeth. Anodontia or the congenital lack of all of
the teeth is quite rare and may be associated with the gene
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
responsible for pegged teeth or missing maxillary incisor
teeth.35 Anodontia may also be the result of irradiation,
chemotherapy, or dioxin. There are numerous syndromes
associated with the congenitally absent teeth. Most notably
these include Down syndrome, Wolf-Hirshhorn syndrome,
holoprosencephaly, Kallmann syndrome, ectodermal
dysplasia, lacrimo-auriculo-dento-digital syndrome, Rieger
syndrome, Johansson-Blizzard syndrome, and Wilkie oculo-
facio-cardio-dental syndrome.
Hypodontia is having ⬍6 congenitally missing teeth,
whereas oligodontia is having ⱖ6 congenitally missing
teeth. The best known of the “missing teeth” syndromes is
ectodermal dysplasia, in which the teeth are often small,
misshaped, and conoid. Oligodontia has been associated
with mutations in MSX1, PAX9, WNT10A and B, and axis
inhibition protein (AXIN2).36
Supernumerary teeth are extra teeth that develop despite
a normal complement of permanent teeth. When they occur
between the permanent incisor teeth, they are referred to as
mesiodentes, and these represent nearly 80% of the cases. A
supernumerary fourth molar tooth and an extra bicuspid
tooth are the next most common supernumerary teeth.37,38
Hyperdontia is the presence of more than the normal
complement of 32 teeth. It is believed to be associated with
excess dental lamina. This most commonly occurs in cases
of cleidocranial dysplasia, and it is characterized by small or
absent clavicles, short stature, delayed closure of the fonta-
nelles, and hyperdontia. There can be delayed tooth erup-
tions and failure to exfoliate the deciduous teeth. More than
50 teeth have been reported in some cases.39 In the Gardner
syndrome, there can be supernumerary teeth, missing teeth,
long pointed tooth roots, especially in the molar teeth. In
the Nance-Horan syndrome, there can be “screwdriver-
shaped” supernumerary teeth.40 In the hyperimmuno-
globulin E syndromes, there can be retained primary
teeth.41,42
Taurodontism refers to morphologically abnormal teeth,
most often found in the molar teeth. They can occur as
hyper-, hypo-, or mesotaurodontism. These alterations can
occur as isolated events or as part of syndromes, for exam-
ple, otodental dysplasia, ectodermal dysplasia, tooth and
nail syndrome.43
Fusion refers to 2 adjacent teeth joined together to form
a single large tooth. Gemination refers to a single tooth
germ forming 2 teeth in the form of a large tooth. If a
patient has a large tooth and there is a missing tooth, then it
is likely fusion. If there are no missing teeth, it is likely
gemination. Dilaceration refers to an abnormal deviation in
a tooth root, and it is associated with trauma to the devel-
oping tooth bud. Concrescence refers to the joining of the
cementum of 2 adjacent teeth, thereby fixing these teeth
together. Flexion of the tooth roots can occur, usually as a
result of trauma. The roots are all deviated to one side.
There can be microdontia, which most often affects the
upper lateral incisor teeth and the third molar teeth. Rarely,
兩 385
Fig 22.Drawing shows the range of the dates for eruption of the deciduous teeth and the permanent teeth (modified with permission from Netter FH.
Atlas of Human Anatomy. 5th ed. Philadelphia, PA: Saunders Elsevier; 2011. Plate 56. Additional data from Putz R, Pabst R, eds. Sobotta Atlas of Human
Anatomy Volume 1: Head, Neck, Upper Limb. 13th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000. Figs 187 and 188, p 105 and from the
Forensic Medicine for Medical Students Web site. http://www.forensicmed.co.uk).

Fig 23. Drawings of various malformations that can affect the teeth.

macrodontia (megadontia) can occur, and it is often asso- dysplasia as well as with incontinentia pigmenti and con-
ciated with acromegaly.44 genital syphilis. Pitted teeth can occur in tuberous sclerosis,
Abnormal tooth morphology can appear as pegged- Gorlin syndrome, tricho-dento-osseous syndrome, and the
shaped teeth that can occur in hypohidrotic ectodermal Herlitz variant of junctional epidermolysis. There can be

386 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org

Fig 24. Drawings illustrate Oehlers classification of dens invaginatus.
screwdriver teeth or Hutchinson teeth, which are classically
associated with congenital syphilis.40
There are abnormalities of the thickness of cementum,
ranging from an absence (cemental aplasia) or paucity of
dentin (cemental hypoplasia) to an excessive deposition of
cementum (cemental hyperplasia or hypercementosis). Hy-
percementosis can be generalized and affect numerous
teeth, or it may be more localized. When the jaws are
involved with Paget disease, there is often associated
hypercementosis.45,46
Dens invaginatus is a developmental malformation that
results from an invagination of the enamel organ into the
dental papilla before mineralization. This starts at the
crown and can occasionally extend into the root. It most
often occurs in the permanent maxillary lateral incisors but
also occurs in the maxillary central incisors, premolars, ca-
nines, and least often in the molar teeth.47 Although several
theories have been proposed regarding the etiology of dens
invaginatus, the theory and classification by Oehlers48,49
are the most often quoted. He suggested that a distortion of
the enamel organ occurs during tooth development, which
results in a deep protrusion of a part of the enamel organ,
which results in an enamel-lined channel ending in the den-
tal pulp, with or without an associated irregular crown
morphology.48,49
Other theories suggest that there is a rapid and aggressive
proliferation of a part of the internal enamel epithelium that
invades the dental papilla. Also proposed as an etiology is
that there is a focal failure of growth of the internal enamel
epithelium, which allows the surrounding normal epithe-
lium to proliferate and engulf the static region. External
forces on the developing tooth as well as genetic etiologies
have also been proposed.47 There are 2 types of dens invagi-
natus that have been described. The more common coronal
Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
type is caused by an invagination of all the layers of the
enamel organ into the dental papilla. In the radicular type,
there is a folding of Hertwig sheath into the developing
root.47 Classification of dens invaginatus by Oehlers is il-
lustrated in Figure 24.48
Although overall rare, there are a number of inherited
abnormalities that affect the size, shape, position, and num-
ber of teeth. In general, the genetic control of dental devel-
opment can be categorized as affecting the type, size, or
position of each tooth, or it can specifically affect the dentin
and the enamel of the tooth. Some mutations can also lead
to syndromes associated with the dental abnormalities. As
an example, the genes MSX1 and AXIN2 are associated
with early tooth development and tooth agenesis, but they
are also associated with cleft palates. Conversely, genes in-
volved in enamel development such as amelogenin X-linked
protein coding gene (AMELX), enamelin a protein coding
gene (ENAM), MMP20, and kallikrein-related peptidase
4 (KLK4), or dentin development (DSPP) are highly con-
served for the teeth.36,40
An example of an enamel-inherited abnormality is
amelogenesis imperfecta (AI), a genetically and clinically
heterogeneous group of disorders that primarily affect the
formation of enamel. Based on the enamel appearance, AI
can be classified as hypoplastic (a secretory defect), hy-
pocalcified (a mineralization defect), or hypomaturation (a
protein-processing and crystallite maturation defect). The
teeth can be pitted or grooved and are more likely to be
worn down or break. AI affects mutations to the genes
AMELX, ENAM, and MMP20.50
Genetic abnormalities that affect dentin have been clas-
sified as dentinogenesis imperfecta (DGI) types I–III and
dentin dysplasia (DD) types I and II. DGI type I is the dental
disorder found in osteogenesis imperfecta, with the teeth
兩 387
usually having a brownish discoloration, fractured enamel,
and secondary attrition.51 In Ehlers-Danlos syndrome,
there can be multiple tooth agenesis, dentin structural
anomalies, and dysplastic roots. In Goldblatt syndrome,
there can be opalescent deciduous teeth.40
Some of the syndromes associated with AI and enamel
hypoplasia include tricho-dento-osseous syndrome, with
thin, pitted, hard enamel, enlarged pulp chambers, and tau-
rodontism. This syndrome may be linked to the DLX3
gene. There are reports of cone-rod dystrophy and AI,
Kohlschütter-Tönz syndrome, a neurodegenerative syn-
drome associated with yellow teeth. AI is also associated
with nephrocalcinosis, vitamin D dependent, and D-resis-
tant rickets with enamel hypoplasia, and autoimmune poly-
endocrinopathies with enamel hypoplasia.40
DGI types II and III as well as DD type II have been
mapped to chromosome 4q21, and mutations in the dentin
sialophosphoprotein gene have been demonstrated to cause
these abnormalities. DD type I, also referred to as radicular
DD or rootless tooth, typically has conical-shaped teeth. In
general, patients with DD and DGI have discolored, either
bluish-gray or yellowish-brown, teeth that are more prone
to erode or break than normal teeth.36
Syndromes associated with dentin abnormalities include
hyperphosphatemic familial tumoral calcinosis in which the
teeth have DD with short bulbous roots, pulp stones, and
partial obliteration of the pulp cavity. There is familial hy-
pophosphatemic vitamin D–resistant rickets, in which the
patients have enlarged pulp chambers, root dysplasias,
and multiple periodontal abscess. Patients with Seckel
syndrome have atrophic or absent teeth and enamel
hypoplasia.
In the rare congenital erythropoietic porphyria, there can
be delayed eruption of teeth as well as a reddish coloration
of the teeth (erythrodontia).52 In pachyonychia congenita,
the infants have premature or natal teeth that are present at
birth.53 There are also a variety of medication- and nutri-
tional-related dental problems. Among the most commonly
reported are the gray-greenish discolorations that occur in
the mid portion of the permanent teeth with minocycline
administration. Similarly, there is the brownish discolor-
ation of the upper third of the permanent teeth found after
the administration of tetracycline.54
PERIODONTAL DISEASE AND CAVITIES
The primary thrust of this review was the embryology and
resultant anatomy of human teeth. Also reviewed were
some of the abnormalities and genetic diseases that are as-
sociated with tooth abnormalities. However, the most com-
monly encountered dental diseases are gingivitis, periodon-
titis, and cavities. With this in mind, a brief review of these
topics seemed in order.
Shortly after a tooth is cleaned, a conditioning film of
proteins and salivary glycoproteins is adsorbed rapidly onto
the tooth surface. This is the acquired enamel pellicle.55 The
adsorption of these salivary constituents occurs within min-
388 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org
utes after the pellicle is removed by tooth cleaning, and the
adsorbed material eventually become transformed into a
highly insoluble coating. Plaque formation involves the in-
teraction between early bacterial colonizers and this pelli-
cle, which results in the formation of a biofilm (Fig 25).
The first bacteria to attach to the pellicle glycoproteins
are gram-positive cocci, followed by gram-positive rods.
These bacteria are able to replicate in the oxygen-rich envi-
ronment of the oral cavity, and they produce the enzyme
glucosyltransferase, which converts sucrose into exopoly-
saccharides. The exopolysaccharides create an environment
that allows other bacteria to attach to the initial colonies as
well as protecting them from the acidic environment of the
oral cavity. As the plaque begins to develop and expand,
oxygen can no longer diffuse into the colonies, and, after a
few days, anaerobic gram-negative bacteria begin to colo-
nize the plaque.
After several weeks, they grow together and form colo-
nies known as corncobs (Fig 25). This anaerobic environ-
ment allows facultative anaerobes, such as Streptococcus
mutans and Lactobacilli, to degrade sucrose via fermenta-
tion pathways, and these bacteria also produce lactic acid as
a metabolic byproduct. If the lactic acid concentration be-
comes high enough, it can cause the pH around the plaque
to drop and gingivitis, periodontitis, and enamel deminer-
alization can occur. The bacterial accumulation is most
common around irregularities of the tooth surface, such as
cracks, and along the gingival margin, likely areas that are
not routinely removed by cleaning.55-57 This accumulation
of bacteria in the biofilm is known as plaque, which is not
calcified (Fig 26).
Specifically, the early colonizing bacteria attach to the
surface of the pellicle as well as to each other. They cluster
together to form sessile mushroom-shaped microcolonies
that are attached to the surface at a narrow base. Each
microcolony is a small, independent community that con-
tains thousands of compatible bacteria. Different micro-
colonies may contain different combinations of bacterial
species. As the biofilm matrix grows, it is penetrated by fluid
channels that conduct the flow of nutrients, waste products,
enzymes, metabolites, and oxygen (Fig 25). The microcolo-
nies within the biofilm have microenvironments, with dif-
fering pH, nutrient availability, and oxygen concentrations.
The bacteria in a biofilm send out chemical signals that
trigger the bacteria to produce proteins and enzymes that
help the intraoral biofilm bypass host defense systems.
Tartar is the result of the mineralization and petrification
of the strongly adherent soft plaque deposits. In humans,
tartar can occur both above (supragingival) and below (sub-
gingival) the gumline, and, unlike dental plaque, whose soft
mat of bacteria can be removed by tooth brushing and
flossing, the physical properties of dental calculi make it
virtually impossible to remove without tooth scaling and
polishing (Fig 26). Chemical analysis of the plaques shows
that mineralization occurs rapidly, usually in ⬍2 weeks,
and calcium phosphate crystals contribute up to 80% of the
Fig 25. Stages of plaque formation. A, Serial drawings show the progressive stages of bacterial colonization during plaque development; the plaque
may become so thick that it is visible to the unaided eye; these plaques are gelatinous and firmly adherent to the enamel; once fully developed,
dispersion of bacteria can occur (modified with permission from Ritter AV, Eidson RS, Donovan TE. Chapter 2: Dental caries: etiology, clinical
characteristics, risk assessment, and management. Pocket Dentistry Web site. https://pocketdentistry.com/2-dental-caries-etiology-clinical-
characteristics-risk-assessment-and-management. Fig 2–5). B, A close-up drawing of early pellicle and plaque shows the structure of the biofilm with
fluid channels.

weight of these deposits. Although tartar adheres strongly
to teeth, its hardness is only 10%–20% that of enamel.58
Gum recession has been attributed to a number of
causes, primarily poor oral hygiene and forceful brushing.
At the gingival margin, morphologic changes develop that
lead to cleft formation and gum recession. This occurs as a
result of a mononuclear cell infiltration of the gum connec-
tive tissue, which causes a breakdown of the connective
tissue and leads to a localized proliferation of the epithelium
into the site of connective tissue destruction. This prolifer-
ation of the epithelial cells results in a gradual retraction of
the epithelial surface, which is clinically manifest as a reces-
sion. As the gum recedes, there is a loss of cementum, which
results in exposure of the dentinal tubules and causes “den-
tinal hypersensitivity” (Figs 15 and 27).59-61
The term periodontal disease usually refers to the com-
mon inflammatory disorders of gingivitis and periodontitis,
both of which are caused by pathogenic microflora in the
biofilm or dental plaque. It is estimated that 90% of the
worldwide population is afflicted with some form of these
diseases. Gingivitis is the mildest form of periodontal dis-
ease and is highly prevalent and readily reversible by good
oral hygiene. It affects 50%–90% of adults worldwide.
When the inflammation extends deep into the tissues and
results in a loss of the tooth’s supporting connective tissue
and alveolar bone, it is known as periodontitis.62
Once the enamel has been penetrated by pathogenic bac-
teria, the bacteria can penetrate the dentin and eventually
spread down the tooth roots. The invasion of living bacteria
into the root canal system of a tooth is necessary for the devel-
opment of a periapical lesion, and the first of these lesions to
develop is the periapical granuloma, which contains chronic
inflammatory cells. In fact, in these patients, bacteria are al-
ways present at some level of the root canal, colonizing in
necrotic debris that lines the canal walls and infiltrating the
disintegrated tissue filling the canal lumen. However, although

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Fig 26. The development of gingivitis and cavities. A, The drawing shows a normal tooth and gum on the left side of the center tooth. On the right side
of the tooth, there is inflamed gum with a resorption pocket and some alveolar bone destruction. Also shown are areas of plaque and, below them,
tartar. B, The drawing shows supragingival and subgingival tartar, as well as inflammation of the gum and a pocket between the gum and the tooth. C,
Typical cracks in the enamel and dentin are shown. If present, these are primary areas for plaque and tartar to develop.

Fig 27. Serial drawings show the progression from a healthy gum through gingivitis, then early and advanced periodontitis.

there are substantial amounts of bacteria in the canal lumen of
these teeth, the periapical granuloma is free of bacteria. In
addition, there is growing evidence that, despite the presence
of a periapical lesion, the pulp tissue in the apical part of the
root may still be vital (Fig 28).
A periapical lesion consists of acute and chronic inflam-
matory cells in variable concentrations, and it may contain
epithelial strands that can develop into a periapical (radic-
ular) cyst. In terms of treatment, when a lesion is diagnosed
as a cyst, it is important to establish its relationship to the
apical foramen of the involved tooth. There are 2 types of
these periapical cysts: the true cyst, which has a cavity that
is completely surrounded by epithelium and not directly
connected to the tooth apical foramen, and the pocket cyst,

390 兩 Neurographics 2018 September/October;8(5):369 –393; www.neurographics.org

Fig 28. Serial drawings show the progression from an initial cavity formation to an apical abscess.

which is an epithelial-lined cavity connected to the apical
foramen of the tooth. If the periapical granuloma or cyst
becomes infected, then a periapical abscess develops (Fig
28). These periapical lesions usually develop in nonvital
teeth, and the periapical cysts may remain even after the
involved tooth has been extracted. In such cases, the re-
maining cyst is called a residual cyst.63
There are a variety of microorganisms that can contrib-
ute to the pathogenesis of periodontal disease in different
populations and individuals. In addition, there are several
genetic and environmental effects that are associated with
periodontal diseases. There are rare syndromes that can
affect phagocytes, epithelial structure, connective tissue,
and teeth. The Haim-Munk and the Papillon-Lefèvre syn-
dromes are rare autosomal recessive disorders that are as-
sociated with periodontitis and the loss of both deciduous
and permanent teeth. In addition, the Chediak-Higashi,
Ehlers-Danios, Kindlers and Cohen syndromes all can have
severe periodontal manifestations.62,64
People who smoke are much more likely to develop peri-
odontitis than are nonsmokers. There is also a small asso-
ciation of periodontitis with alcohol consumption. In addi-
tion, people with HIV infection, diabetes, poor nutrition,
and emotional stress all have a higher incidence of peri-
odontal diseases.62,65
CONCLUSIONS
The embryology of the teeth was reviewed. The variation in
individual tooth development was also discussed, as were
some of the various abnormalities that can affect the teeth.
Because the teeth play an important role in the everyday life
of humans, this review will, it is hoped, shed light not only
on the development of teeth but also on their functional
importance.

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ACKNOWLEDGMENTS
I want to thank Ophir Klein, MD, PhD, for his review and
comments of this manuscript.
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