Neural crest cells / dental implant courses by Indian dental academy

INDIAN DENTAL ACADEMY
Leader in continuing Dental
Education
www.indiandentalacademy.com

LEARNING OBJECTIVES
At the end of the seminar, the learner should be able to :
 Know the history and evolution of neural crest.
 Describe the formation of neural crest.
 Describe the migration of neural crest.
 Know the derivatives of neural crest and
 Its clinical implications.

Contents
 Introduction
 History
 Evolution
 Formation of neural crest
 Migration of neural crest
 Derivatives of neural crest
 Applied

Introduction
 Neural crest cells are originally located at the lateral margins of
the neural plate along the length of the embryo.
 Neural crest cells are a transient, multipotent, migratory cell
population.
Unique to vertebrates that gives rise to a diverse cell lineage
including
 Melanocytes,
 Craniofacial cartilage and bone, smooth muscle,
 Peripheral and enteric neurons and glia.

History
 First described in the chick embryo by Wilhelm His in
1868 as "the cord in between" because of its origin
between the neural plate and non-neural ectoderm.
 First named as ganglionic crest since its final destination
was each lateral side of the neural tube where it
differentiated into spinal ganglia.
 During the first half of the 20th century the majority of
research on neural crest was done using amphibian
embryos.

Evolution
 Although derived from ectoderm, the neural crest has
sometimes been called the “fourth germ layer” because of
its importance in derivation of different organs and tissues.
 Neural crest cells have also been considered the
developmental factors (along with input from Hox genes)
that “make humans human” because of their role in
determining facial structure.

Several structures that distinguish the vertebrates from other
chordates are formed from the derivatives of neural crest cells.
In Gans and Northcut's "New head" theory, they argued that the
presence of neural crest was the basis for vertebrate specific
features, such as sensory ganglia and cranial skeleton.
Furthermore, the appearance of these features was pivotal in
vertebrate evolution because it enabled a predatory lifestyle.

 FORMATION OF NEURAL CREST CELL
 Fertilization of the ovum occurs in the ampulla of the
uterine tube.
 The two cells formed undergo a series of divisions .
 One cell divides first so that a 3 cell stage of the embryo is
formed .

 The 3 cell stage is followed by 4 cell stage, a 5 cell stage,
etc . This process of subdivision of the ovum into smaller
cells is called cleavage.
 As the cleavage proceeds the ovum comes to have 16
cells, when it looks like a mulberry and is called the
morula.
 The morula consists of an inner cell mass which is
surrounded by an outer layer of cells.

 The cells of the outer layer gives rise to trophoblast.
 The inner cell mass gives rise to embryo proper and is
therefore known as embryoblast.
 The cells of the trophoblast help to provide nutrition to the
embryo .

 Some fluid passes into the morula from the uterine cavity
and partially separates the cells of the inner cell mass from
those of the trophoblast.
 As the quantity of fluid increases the morula acquires the
shape of a cyst called blastocyst .
 The cavity of the blastocyst is called blastocoele.

 The side of the blastocyst to which the inner cell mass is
attached is called the embryonic pole while the opposite
side is called abembryonic pole.
 Some cells of the inner cell mass differentiate into
flattened cells , that comes to line its free surface. These
constitute the endoderm, the first germ layer.

 The remaining cells of the inner cell mass becomes
columnar and form the second germ layer i.e the
ectoderm.
 The amniotic cavity is formed as a space appears between
the ectoderm and the trophoblast . This cavity is filled
with amniotic fluid or liquor amnii.
 The roof of this cavity is formed by amniogenic cells,
derived from trophoblast while the floor is formed by
ectoderm.

 The flattened cells arising from the endoderm spread and line
the inside of the blastocystic cavity, giving rise to a cavity
called the primary yolk sac.
 The cells of the trophoblast give origin to a mass of cells
called the extra-embryonic mesoderm, which come to lie
between the trophoblast and the flattened endodermal cells
lining the yolk sac,thus separating these cells from each other.

 Some cavities appear in the extra-embryonic
mesoderm,which join each other to form a large cavity
called the extra-embryonic coelom or chorionic cavity.
 With its formation the extra-embryonic mesoderm is split
into two layers.
 The part lining the inside of the trophoblast and the
outside of the amniotic cavity is called the somatopleuric
extra-embryonic mesoderm.

 The part lining the outside of the yolk sac is called the
visceral splanchnopleuric extra –embryonic mesoderm.
 With the appearance of the extra-embryonic
mesoderm,and later the extra-embryonic coelom,the yolk
sac becomes much smaller than the before and is now
called the secondary yolk sac.

 The alteration in size is accompanied by a change in the
nature of the lining cells.These cells are no longer
flattened but become cubical.
 At this stage,the embryo proper is a circular disc
composed of two layers of cells:the upper layer towards
the amniotic cavity is the ectoderm,the cells of which are
columnar, while the lower layer which is towards the yolk
sac is endoderm,made up of cubical cells.

 At one circular area near the margin of the disc,the
cubical cells of the endoderm become columnar . This
area is called the prechordal plate.
 The appearance of the prechordal plate determines the
central axis of the embryo,which divides the embryo into
right and left halves and also helps to distinguish its future
head and tail ends.

 Soon after the formation of the prochordal plate some of
the ectodermal cells lying along the central axis,near the
tail end of the disc, begin to proliferate and form an
elevation that bulges into the amniotic cavity .
 This is called the primitive streak,which is at first a
rounded or oval swelling but with elongation of the
embryonic disc it becomes a linear structure lying in the
central axis of the disc.

 The cells that proliferate in the region of primitive streak
pass sideways,pushing themselves between the ectoderm
and endoderm.
 These cells form the intra-embryonic mesoderm or
secondary mesoderm which is the third germ layer.

 The process of formation of the primitive streak and the
intra-embryonic mesoderm by the streak is referred to as
gastrulation.
 The intra-embryonic mesoderm spreads throughout the
disc except in the region of the prochordal plate.
 In the region of the prochordal plate, the ectoderm and the
endoderm remain in contact.

 In later development, the ectoderm and endoderm mostly
persist as a lining epithelium.
 On the other hand, the bulk of the tissues of the body is
formed predominantly from mesoderm.
 As there is no mesoderm in the prochordal plate , this
region remains relatively thin and later forms the bucco-
pharyngeal membrane.

 The primitive streak gradually elongates, along the central
axis of the embryonic disc .
 The disc also elongates and becomes pear shaped .
FORMATION OF THE NOTOCHORD-
 The notochord is a midline structure that develops in the
region lying between the cranial end of the primitive
streak and the caudal end of the prochordal plate.

 During its development, the notochord passes through
several stages that are as follows:
 The cranial end of the primitive streak becomes
thickened.The thickened part of the streak is called the
primitive knot or primitive node or Henson’s node.
 A depression appears in the centre of the primitive knot.
This depression is called the blastopore.

 Cells in the primitive knot multiply and pass cranially in
the middle line, between the ectoderm and endoderm,
reaching up to the caudal margin of the prochordal plate .
These cells form a solid cord called the notochordal
process or head process.
 The cells of this process undergo several stages of
rearrangement, ending in the formation of a solid rod
called the notochord.

 As the embryo enlarges, the notochord elongates
considerably and lies in the midline,in the position to be
later occupied by the vertebral column.
 The notochord does not give rise to the vertebral column,
rather most of it disappears except in the region of each
intervertebral disc where it persists as the nucleus
pulposus .

FORMATION OF THE NEURAL TUBE
 The part of the ectoderm that is destined to give origin to
the brain and spinal cord,can be distinguished while the
embryo is still in the form of a three layered embryonic
disc.
 This ectoderm is situated on the dorsal aspect of the
embryonic disc,in the midline , and overlies the
notochordal process.
 It soon thickens to form the neural plate.

 The neural plate becomes depressed along the midline, as
a result of which the neural groove is formed.
 This groove becomes progressively deeper.
 At the same time,the two edges of the neural plate come
nearer to each other and eventually fuse, thus converting
the neural groove into the neural tube.

 Even before the neural tube has completely closed,it is
divisible into an enlarged cranial part and a tubular caudal
part.
 The enlarged cranial part forms the brain while the caudal
tubular part forms the spinal cord.
THE NEURAL CREST
 Neural crest cells are neuro-ectodermal in origin. They
start differentiating during the formation of neural tube in
the third week of intrauterine life.

 At the time when the neural plate is being formed, some
cells at the junction between the neural plate and the rest
of the ectoderm becomes specialized (on either side )to
form primordia of the neural crest.
 With the separation of the neural tube from the surface
ectoderm, the cells of the neural crest appear as groups of
cells lying along the dorsolateral sides of the neural tube.

 The neural crest cells soon become free by losing the
property of cell to cell adhesiveness.
 They migrate to distant places throughout the body.
 The emergence of neural crest was important in vertebrate
evolution because many of its structural derivatives are
defining features of the vertebrate clade.

INDUCTION OF MIGRATION OF NEURAL CREST
CELL
 A molecular cascade of events is involved in establishing
the migratory and multipotent charateristics of neural crest
cells.
 This gene regulatory network can be subdivided into
following four subnetworks –
First extracellular signalling molecules, secreted from
adjacent epidermis and underlying mesoderm such as
wnts,BMPS and Fgfs separate the non-neural ectoderm
from the neural plate during neural induction.

 The promoter region of Slug,which is a neural crest
specific gene contains a binding site for transcription
factors involved in the activation of Wnt dependent target
gene,suggestive of direct role of Wnt signalling in neural
crest specification.
Second is the formation of neural plate border specifiers-
 Signalling events that establish the neural plate border
lead to the expression of a set of transcription factors
delineated here as neural plate border specifiers.

 These molecules include Zic factors, Pax3/7 ,Dlx5,
Max1/2 which may mediate the influence of Wnts, BMP
and Fgfs.
 These genes are expressed broadly at the neural plate
border region and preceede the expression of bonafide
neural crest markers.
Third is the expression of neural crest specifiers-
 Following the expression of neural plate border specifiers
there is expression of neural crest specifiers which is
controlled by a collection of genes including Slug ,Snail,
FoxD3,Sox10,Sox9AP2and C-Myc.

 This suite of genes designated here as neural crest
specifiers are activated in emergent neural crest cells.
Finally there is expression of neural crest effector genes-
The neural crest specifiers turn on the expression of
effector genes which confer certain properities such as
migration and multipotency.
 Two neural crest effectors,RhoGTPases and cadherins
determine the cell morphology and adhesive properties .

NEURAL CREST CELL MIGRATION-
 A number of extracellular matrix molecules have been
implicated in the control of neural crest cell migration.
 Molecules like laminin ,fibronectin and integrin,a family
of cell surface receptors for ECM molecules are present
along the pathway of neural crest cell migration and hence
good candidates for regulating their migration.

 Neural crest cell adhesion fibronectin and collagen are
mediated by RGD dependent integrin and that of laminin
are mediated by β1 containing integrin.
 Neural crest cells express both neural cell adhesion
molecule and N-cadherin before migration but lose both
molecules during emigration from the neural tube and
express little or none while migrating.

Cell lineages
 Neural crest can be divided into four main functional
domains,
 cranial neural crest,
 trunk neural crest,
 vagal and sacral neural crest, and
 cardiac neural crest.

 Cranial neural crest migrates dorsolaterally to form the
craniofacial mesenchyme that differentiates into various
cranial ganglia and craniofacial cartilages and bones.
 These cells enter the pharyngeal pouches and arches
where they contribute to the thymus, bones of the middle
ear and jaw and the odontoblasts of the tooth primordia.

Differentiation of cranial neural crest cells. As CNC cells migrate into the
craniofacial region, these ectomesenchymal progenitors may give rise to an array of
tissue types, such as odontoblasts, chondroblasts, osteoblasts, etc. Both ectoderm
and endoderm of the branchial arch provide signaling instructions for the fate
specification of these progenitor cells. CNC cells also contribute to the formation
of neural tissues, such as sensory neurons and cranial nerve ganglia.

 Trunk neural crest give rise to two populations of cells.
 One group of cells fated to become melanocytes migrates
dorsolaterally into the ectoderm towards the ventral
midline.
 A second group of cells migrates ventrolaterally through
the anterior portion of each sclerotome. The cells that stay
in the sclerotome form the dorsal root ganglia,
 whereas those that continue more ventrally form the
sympathetic ganglia, adrenal medulla, and the nerves
surrounding the aorta.

 Vagal and sacral neural crest
 The vagal and sacral neural crest cells develop into the
ganglia of the enteric nervous system, also known as the
parasympathetic ganglia.

Cardiac neural crest
 Cardiac neural crest develops into melanocytes, cartilage,
connective tissue and neurons of some pharyngeal arches.
 Also, this domain gives rise to regions of the heart such as
the musculo-connective tissue of the large arteries, and
part of the septum, which divides the pulmonary
circulation from the aorta.
 The semilunar valves of the heart are associated with
neural crest cells according to new research.

Neural crest derivatives
 Postganglionic sympathetic neurones.
 Schwann cells.
 Neurones of the dorsal nerve root ganglia.
 The specific cells of the adrenal medulla.
 Chromaffin tisue.
 The pigment cells of the skin.
 The dendritic cells of the skin.

 Piamater and arachnoidmater .
 Mesenchyme of the dental papilla,odontoblasts and
dentine.
 Bones of the face and parts of the vault of the
skull(frontal,parietal,squamous temporal,part of the
sphenoid, maxilla,zygomatic ,nasal, vomer ,palatine and
mandible).
 Dermis ,smooth muscle and fat of face and ventral aspect
of neck.

 Muscles of the ciliary body.
 Sclera and choroid of the eye .
 Substantia propria and posterior epithelium of cornea.
 Connective tissues of thyroid ,parathyroid ,thymus and
salivary glands.
 Derivatives of the first, second and third pharyngeal
cartilages.
 C cells of the thyroid gland.

CRANIOFACIAL DEFECTS INVOLVING NEURAL
CREST CELLS-
It could arise from-
 1.Total failure of the development of neural crest because
of the failure of the inductive interaction that specify
neural crest cells during neuralation.
 Such a failure would almost certainly be lethal or result in
major structural abnormalities to the entire embryo.

 2.Abnormalities in neural crest cell migration because of
defects in neural crest cell themselves or abnormal
extracellular matrix.
 Such defects result in major structural abnormalities to
entire units such as the face,cranium,jaws,ears, heart or
peripheral nervous system.
 3.Abnormal differentiation of neural crest cells because of
intrinsic problems such as altered cell surface
adhesion,defective structural gene or defective inductive
interaction.

 Due to this, individual neural crest derivatives such as
bones,cartilage,teeth or gland would either fail to form or
form abnormally.
 4.Abnormalities in tissues such as muscle,nerves or blood
vessels with which neural crest cell derivatives normally
interact.
 Minor structural defects or defective function would likely
to result.

 Most common example of defective migration of neural
crest cell is Treacher Collin’s Syndrome.

Treacher Collins Syndrome
Treacher Collins syndrome, also known as
manidibulofacial dysostosis, is an autosomal dominant
disorder which derived affects the development of the
head and face.

 The syndrome is charaterized by
 Hypoplasia of the facial bones,especially of the malar
bones and mandible.
 Malformation of the external ear and occasionally of the
middle and internal ears.
 Macrostomia ,high palate and abnormal position and
malocclusion of teeth.
 Blind fistula between the angles of the ear and the angles
of mouth.

 Atypical hair growth in the form of a tongue shaped
process of the hairline extending towards the cheek.
 The characteristic faces of the patients are described as
being birdlike or fishlike in nature.

CLEFT LIP AND PALATE
 conditions arise during gestation and are the result of
improper neural crest cell migration. When this occurs,
tissues of the lip and/or palate are left unjoined.
 Combined, cleft palate and cleft lip are among the most
common birth defects world wide.
 Approximately 1 in every 700 babies born has either a
cleft lip, cleft palate or a combination of the two.
 These clefts can range in from mild to severe.

Cleft Palate and Cleft Lip
Unilateral cleft lip
Cleft palate
Bilateral cleft lip
Unilateral cleft lip & palate
Bilateral cleft lip & palate

 There are many disease processes associated with
defective proliferation , differentiation and induction of
neural crest cells.
 Defective proliferation is due to inhibition of cell division
following exposure of embryo to x-ray,steroid hormone or
alcohol during pregnancy.
 Neurocristopathies is the term generally used by the
physicians to denote the different diseases associated with
defective proliferation , differentiation and induction of
neural crest cells.

 Neurocristopathy is a term coined by Robert P. Bolande
in 1974, referring to a diverse class of pathologies that
may arise from defects in the development of tissues
containing cells commonly derived from the embryonic
neural crest cell lineage.

 Accepted examples include : Waardenburg syndrome
 Hirschsprung disease
 Ondine's curse (congenital central hypoventilation
syndrome),
 pheochromocytoma
 multiple endocrine neoplasia
 neurofibromatosis type I
 Axenfeld-Rieger syndrome
 Goldenhar syndrome ( hemifacial microsomia)
 craniofrontonasal syndrome
 congenital melanocytic nevus
 congenital heart defects .

 Waardenburg syndrome is a group of genetic conditions that
can cause hearing loss and changes in coloring (pigmentation)
of the hair, skin, and eyes.
 People with this condition often have very pale blue eyes or
different colored eyes, such as one blue eye and one brown eye.
Sometimes one eye has segments of two different colors.
 Distinctive hair coloring (such as a patch of white hair or hair
that prematurely turns gray) is another common sign of the
condition.
 The features of Waardenburg syndrome vary among affected
individuals, even among people in the same family.

Symptoms associated with
Hirschsprung disease include:
Bowel Movement difficulty
Inability to pass a stool up to 48
hours post-birth
Low weight gain
Rare and explosive stools
Vomit
Increasingly worse constipation
Diarrhea
Swollen stomach
Flatulence .

 Ondine’s curse (also known as congenital central
hypoventilation syndrome) is a rare, severe form of sleep
apnea in which the affected individual completely stops
breathing when falling asleep. Central hypoventilation
affects about one in 30 million people, which means only
several hundred people have it in the world.
 A genetic mutation appears to be the underlying cause.

 It is thought to occur when the brain fails to prompt
breathing, as may also be seen in central sleep apnea.
 Treatment of this condition involves the use of a ventilator
connected to a tracheostomy tube at the front of the throat
whenever the affected individual goes to sleep, even
during naps. If this were not used, someone with this
condition could die anytime they fall asleep.

 A pheochromocytoma or phaeochromocytoma (PCC) is
a neuroendocrine tumor of the medulla of the adrenal
glands (originating in the chromaffin cells), or extra-
adrenal chromaffin tissue that failed to involute after birth
 It is associated with secretion of excessive amounts of
catecholamines, usually noradrenaline (norepinephrine),
and adrenaline (epinephrine) to a lesser extent.

 The signs and symptoms of a pheochromocytoma are
those of sympathetic nervous system hyperactivity,
including:
 Skin sensations
 Flank pain
 Elevated heart rate
 Elevated blood pressure
 Palpitations
 Anxiety often resembling that of a panic attack.

 Diaphoresis (excessive sweating)
 Headaches
 Pallor
 Weight loss
 Localized amyloid deposits found microscopically
 Elevated blood glucose level (due primarily to
catecholamine stimulation) and lipolysis (breakdown of
stored fat) leading to high levels of free fatty acids and the
subsequent inhibition of glucose uptake by muscle cells.

• Craniofrontonasal syndrome is an X-linked syndrome which is
more severe in females than males.
• Often males will have only hypertelorism (far apart eyes).
• Females have frontonasal dysplasia, craniofacial asymmetry, bifid
nasal tip, grooved nails, wiry hair and anomalies of the thoracic
skeleton.
• Most cases arise from mutations in the
gene for EFNB1.

 Goldenhar syndrome (also known as Oculo-Auriculo-
Vertebral (OAV) syndrome) is a rare congenital defect
characterized by incomplete development of the ear, nose,
soft palate, lip, and mandible.
 It is associated with anomalous development of the first
branchial arch and second branchial arch.
 Common clinical manifestations include limbal dermoids,
preauricular skin tags, and strabismus.

 Axenfeld-Rieger syndrome (ARS) is a rare autosomal
dominant disorder (1 : 200000) with variable morphology
characterized by malformations of the anterior segment of
the eye such as Iris hypoplasia, iridocorneal adhesions,
corectopia, polycoria.
 Glaucoma is associated in 50% of the cases .
Craniofacial, dental, and umbilical anomalies are also
regularly reported in connection with ARS .

 Characteristic craniofacial features are maxillary
hypoplasia, hypertelorism, and telecanthus.
 Dental features include hypodontia/oligodontia of primary
and permanent dentition, microdontia, short roots,
taurodontism, and abnormally shaped teeth.

 Three genes have so far been identified to be associated
with ARS.
 The genes FOXC1 and PITX2 encode transcription
factors and are located on chromosomes 6p25 and 4q25,
respectively.
 A third locus for ARS was mapped to chromosome 13q14
but the gene has not yet been identified.

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Neural crest cells / dental implant courses by Indian dental academy

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