Neural crest cells are a temporary group of cells unique to
vertebrate
Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
s that arise from the embryonic
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the ...
germ layer
A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three pr ...
, and in turn give rise to a diverse cell lineage—including
melanocytes
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
M ...
,
craniofacial cartilage and bone,
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mu ...
,
peripheral
A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...
and
enteric neurons and
glia
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...
.
After
gastrulation
Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. B ...
, neural crest cells are specified at the border of the
neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
and the non-neural
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the ...
. During
neurulation, the borders of the neural plate, also known as the
neural folds, converge at the dorsal midline to form the
neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...
. Subsequently, neural crest cells from the roof plate of the neural tube undergo an
epithelial to mesenchymal transition, delaminating from the
neuroepithelium and migrating through the periphery where they differentiate into varied cell types.
The emergence of neural crest was important in
vertebrate
Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
evolution because many of its structural derivatives are defining features of the vertebrate
clade
A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English term ...
.
Underlying the development of neural crest is a
gene regulatory network, described as a set of interacting signals,
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
, and downstream
effector
Effector may refer to:
* Effector (biology), a molecule that binds to a protein and thereby alters the activity of that protein
* ''Effector'' (album), a music album by the Experimental Techno group Download
* ''EFFector'', a publication of the E ...
genes that confer cell characteristics such as multipotency and migratory capabilities.
Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple
cell lineages. Abnormalities in neural crest development cause
neurocristopathies, which include conditions such as
frontonasal dysplasia,
Waardenburg–Shah syndrome, and
DiGeorge syndrome
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...
.
Therefore, defining the mechanisms of neural crest development may reveal key insights into vertebrate evolution and neurocristopathies.
History
Neural crest was first described in the chick embryo by
Wilhelm His Sr. in 1868 as "the cord in between" (Zwischenstrang) because of its origin between the neural plate and non-neural ectoderm.
He named the tissue 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 which was reviewed by Hörstadius (1950) in a well known monograph.
Cell labeling techniques advanced the field of neural crest because they allowed researchers to visualize the migration of the tissue throughout the developing embryos. In the 1960s Weston and Chibon utilized radioisotopic labeling of the nucleus with tritiated thymidine in chick and amphibian embryo respectively. However, this method suffers from drawbacks of stability, since every time the labeled cell divides the signal is diluted. Modern cell labeling techniques such as rhodamine-lysinated dextran and the vital dye diI have also been developed to transiently mark neural crest lineages.
The quail-chick marking system, devised by Nicole Le Douarin in 1969, was another instrumental technique used to track neural crest cells.
Chimeras, generated through transplantation, enabled researchers to distinguish neural crest cells of one species from the surrounding tissue of another species. With this technique, generations of scientists were able to reliably mark and study the
ontogeny
Ontogeny (also ontogenesis) is the origination and development of an organism (both physical and psychological, e.g., moral development), usually from the time of fertilization of the egg to adult. The term can also be used to refer to the st ...
of neural crest cells.
Induction
A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. This
gene regulatory network can be subdivided into the following four sub-networks described below.
Inductive signals
First, extracellular signaling molecules, secreted from the adjacent
epidermis
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...
and underlying
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Embry ...
such as
Wnts
WNTS (1590 AM) is a commercial radio station licensed to Beech Grove, Indiana, and serving the Indianapolis metropolitan area. It broadcasts a Classic Regional Mexican radio format and is owned by Marvin Kosofosky's Continental Broadcast Grou ...
,
BMPs and
Fgfs separate the non-neural
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the ...
(epidermis) from the neural plate during
neural induction.
Wnt signaling has been demonstrated in neural crest induction in several species through gain-of-function and loss-of-function experiments. In coherence with this observation, the
promoter region of slug (a neural crest specific gene) contains a
binding site for
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The ...
s involved in the activation of Wnt-dependent target genes, suggestive of a direct role of Wnt signaling in neural crest specification.
The current role of BMP in neural crest formation is associated with the induction of the neural plate. BMP antagonists diffusing from the ectoderm generates a gradient of BMP activity. In this manner, the neural crest lineage forms from intermediate levels of BMP signaling required for the development of the neural plate (low BMP) and epidermis (high BMP).
Fgf from the
paraxial mesoderm has been suggested as a source of neural crest inductive signal. Researchers have demonstrated that the expression of dominate-negative Fgf receptor in ectoderm explants blocks neural crest induction when recombined with paraxial mesoderm. The understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete.
Neural plate border specifiers
Signaling 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, Msx1/2 which may mediate the influence of Wnts, BMPs, and Fgfs. These genes are expressed broadly at the neural plate border region and precede the expression of bona fide neural crest markers.
Experimental evidence places these transcription factors upstream of neural crest specifiers. For example, in ''
Xenopus
''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-know ...
'' Msx1 is
necessary and sufficient for the expression of Slug, Snail, and FoxD3. Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.
Neural crest specifiers
Following the expression of neural plate border specifiers is a collection of genes including Slug/Snail, FoxD3, Sox10, Sox9, AP-2 and c-Myc. This suite of genes, designated here as neural crest specifiers, are activated in emergent neural crest cells. At least in Xenopus, every neural crest specifier is necessary and/or sufficient for the expression of all other specifiers, demonstrating the existence of extensive cross-regulation.
Moreover, this model organism was instrumental in the elucidation of the role of the Hedgehog signaling pathway in the specification of the neural crest, with the transcription factor Gli2 playing a key role.
Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, a
bHLH transcription factor, is required for mesenchyme differentiation of the
pharyngeal arch structures. Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.
Neural crest effector genes
Finally, neural crest specifiers turn on the expression of effector genes, which confer certain properties such as migration and multipotency. Two neural crest effectors, ''
Rho GTPases'' and ''
cadherins'', function in delamination by regulating cell morphology and adhesive properties. Sox9 and Sox10 regulate neural crest differentiation by activating many cell-type-specific effectors including Mitf, P0, Cx32, Trp and cKit.
Migration
The migration of neural crest cells involves a highly coordinated cascade of events that begins with closure of the
dorsal neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...
.
Delamination
After fusion of the
neural fold to create the
neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...
, cells originally located in the
neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
border become neural crest
cells.
For migration to begin, neural crest cells must undergo a process called delamination that involves a full or partial
epithelial-mesenchymal transition (EMT).
Delamination is defined as the separation of
tissue into different populations, in this case neural crest cells separating from the surrounding tissue.
Conversely, EMT is a series of events coordinating a change from an
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
to
mesenchymal phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
.
For example, delamination in
chick embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
s is triggered by a
BMP/
Wnt cascade that induces the expression of EMT promoting
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The ...
s such as
SNAI2
Zinc finger protein SNAI2 is a transcription factor that in humans is encoded by the ''SNAI2'' gene. It promotes the differentiation and migration of certain cells and has roles in initiating gastrulation.
Function
This gene encodes a member ...
and
FoxD3
Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the ''FOXD3'' gene.
Function
This gene belongs to the forkhead protein family of transcription factors which is characterized by a DNA-binding forkhead ...
.
Although all neural crest cells undergo EMT, the timing of delamination occurs at different stages in different organisms: in
''Xenopus laevis'' embryos there is a massive delamination that occurs when the
neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
is not entirely fused, whereas delamination in the
chick embryo occurs during fusion of the
neural fold.
Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells by
tight junction proteins such as
occludin and
cell adhesion molecules such as
NCAM and
N''-''Cadherin.
Dorsally expressed
BMPs initiate delamination by inducing the expression of the
zinc finger
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struc ...
protein transcription factors
snail
A snail is, in loose terms, a shelled gastropod. The name is most often applied to land snails, terrestrial pulmonate gastropod molluscs. However, the common name ''snail'' is also used for most of the members of the molluscan class Gas ...
,
slug
Slug, or land slug, is a common name for any apparently shell-less terrestrial gastropod mollusc. The word ''slug'' is also often used as part of the common name of any gastropod mollusc that has no shell, a very reduced shell, or only a sma ...
, and
twist.
These factors play a direct role in inducing the
epithelial-mesenchymal transition by reducing expression of
occludin and
N-Cadherin in addition to promoting
modification of
NCAMs with
polysialic acid residues to decrease adhesiveness.
Neural crest cells also begin expressing
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the fo ...
s capable of degrading
cadherin
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...
s such as
ADAM10
A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ''ADAM10'' gene.
Function
Members of the ADAM family are cell surface proteins with a uni ...
and secreting
matrix metalloproteinases (MMPs) that degrade the overlying
basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The bas ...
of the neural tube to allow neural crest cells to escape.
Additionally, neural crest cells begin expressing
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s that associate with
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide str ...
proteins, including
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
,
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
, and
laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
, during migration.
Once the basal lamina becomes permeable the neural crest cells can begin migrating throughout the embryo.
Migration

Neural crest cell migration occurs in a
rostral to
caudal direction without the need of a neuronal
scaffold
Scaffolding, also called scaffold or staging, is a temporary structure used to support a work crew and materials to aid in the construction, maintenance and repair of buildings, bridges and all other man-made structures. Scaffolds are widely us ...
such as along a
radial glial cell
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ol ...
. For this reason the crest cell migration process is termed “free migration”. Instead of scaffolding on
progenitor cell
A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only differ ...
s, neural crest migration is the result of repulsive guidance via
EphB/
EphrinB and
semaphorin
Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorin ...
/
neuropilin
Neuropilin is a protein receptor active in neurons.
There are two forms of Neuropilins, NRP-1 and NRP-2. Neuropilins are transmembrane glycoproteins, first documented to regulate neurogenesis and angiogenesis by complexing with Plexin recept ...
signaling, interactions with the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide str ...
, and
contact inhibition with one another.
While Ephrin and Eph proteins have the capacity to undergo bi-directional signaling, neural crest cell repulsion employs predominantly forward signaling to initiate a response within the
receptor bearing neural crest cell.
Burgeoning neural crest cells express EphB, a
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine k ...
, which binds the EphrinB transmembrane
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
expressed in the caudal half of each
somite
The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide i ...
. When these two domains interact it causes receptor tyrosine phosphorylation, activation of
rhoGTPases, and eventual
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compose ...
rearrangements within the crest cells inducing them to repel. This phenomenon allows neural crest cells to funnel through the rostral portion of each somite.
Semaphorin-neuropilin repulsive signaling works synergistically with EphB signaling to guide neural crest cells down the rostral half of somites in mice. In chick embryos, semaphorin acts in the cephalic region to guide neural crest cells through the
pharyngeal arches. On top of repulsive repulsive signaling, neural crest cells express β1and α4
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s which allows for binding and guided interaction with
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
,
laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
, and
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
of the extracellular matrix as they travel. Additionally, crest cells have intrinsic contact inhibition with one another while freely invading tissues of different origin such as
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Embry ...
.
Neural crest cells that migrate through the rostral half of somites differentiate into
sensory and
sympathetic neurons of the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...
. The other main route neural crest cells take is
dorsolaterally between the
epidermis
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...
and the
dermamyotome. Cells migrating through this path differentiate into
pigment cells
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
M ...
of the
dermis
The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided ...
. Further neural crest cell
differentiation and specification into their final cell type is biased by their
spatiotemporal subjection to morphogenic cues such as BMP, Wnt, FGF,
Hox, and
Notch.
Clinical significance
Neurocristopathies result from the abnormal specification, migration, differentiation or death of neural crest cells throughout embryonic development. This group of diseases comprises a wide spectrum of congenital malformations affecting many newborns. Additionally, they arise because of genetic defects affecting the formation of neural crest and because of the action of
Teratogens
Waardenburg's syndrome
Waardenburg's syndrome is a
neurocristopathy that results from defective neural crest cell migration. The condition's main characteristics include
piebaldism and
congenital deafness
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
. In the case of piebaldism, the colorless
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different d ...
areas are caused by a total absence of neural crest-derived
pigment
A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compou ...
-producing
melanocyte
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
s.
There are four different types of Waardenburg's syndrome, each with distinct
genetic and physiological features. Types I and II are distinguished based on whether or not family members of the affected individual have
dystopia canthorum. Type III gives rise to upper limb abnormalities. Lastly, type IV is also known as Waardenburg-Shah syndrome, and afflicted individuals display both Waardenburg's syndrome and
Hirschsprung's disease. Types I and III are
inherited in an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
fashion,
while II and IV exhibit an
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
pattern of inheritance. Overall, Waardenburg's syndrome is rare, with an
incidence of ~ 2/100,000 people in the United States. All
races and
sexes are equally affected.
There is no current cure or treatment for Waardenburg's syndrome.
Hirschsprung's Disease
Also implicated in defects related to neural crest cell development and
migration is
Hirschsprung's disease (HD or HSCR), characterized by a lack of innervation in regions of the
intestine
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
. This lack of
innervation
A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system.
A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...
can lead to further
physiological
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
abnormalities like an enlarged
colon (
megacolon), obstruction of the
bowels
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, or even slowed growth. In healthy development, neural crest cells migrate into the
gut and form the
enteric ganglia. Genes playing a role in the healthy migration of these neural crest cells to the gut include
RET,
GDNF,
GFRα,
EDN3, and
EDNRB.
RET, a
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine k ...
(RTK), forms a complex with
GDNF and
GFRα.
EDN3 and
EDNRB are then implicated in the same signaling network. When this signaling is disrupted in mice,
aganglionosis, or the lack of these enteric ganglia occurs.
Fetal Alcohol Spectrum Disorder
Prenatal alcohol exposure (PAE) is among the most common causes of
developmental defects. Depending on the extent of the exposure and the severity of the resulting abnormalities,
patients are diagnosed within a continuum of disorders broadly labeled
Fetal Alcohol Spectrum Disorder (FASD). Severe FASD can impair neural crest
migration, as evidenced by characteristic
craniofacial abnormalities including short
palpebral fissures, an elongated upper lip, and a smoothened
philtrum
The philtrum ( la, philtrum from Ancient Greek ''phíltron,'' lit. "love charm"), or medial cleft, is a vertical indentation in the middle area of the upper lip, common to therian mammals, extending in humans from the nasal septum to the tuber ...
. However, due to the promiscuous nature of
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
binding, the mechanisms by which these abnormalities arise is still unclear.
Cell culture
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This t ...
explants of neural crest cells as well as
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
developing
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
embryos
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
exposed to ethanol show a decreased number of
migratory cells and decreased distances travelled by migrating neural crest cells. The mechanisms behind these changes are not well understood, but evidence suggests PAE can increase
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
due to increased
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
ic
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
levels caused by
IP3-mediated
release of calcium from
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
stores. It has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increased
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
. Despite these, and other advances much remains to be discovered about how ethanol affects neural crest development. For example, it appears that ethanol differentially affects certain neural crest cells over others; that is, while craniofacial abnormalities are common in PAE, neural crest-derived
pigment cells
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
M ...
appear to be minimally affected.
DiGeorge syndrome
DiGeorge syndrome
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...
is associated with
deletions or
translocations of a small segment in the
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture ...
chromosome 22
Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing ...
. This deletion may disrupt rostral neural crest
cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular direct ...
or
development. Some defects observed are linked to the
pharyngeal pouch system, which receives contribution from rostral migratory crest cells. The
symptoms
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
of DiGeorge syndrome include
congenital heart defects,
facial defects, and some
neurological and
learning disabilities. Patients with 22q11 deletions have also been reported to have higher incidence of
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withd ...
and
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated wit ...
.
Treacher Collins Syndrome
Treacher Collins Syndrome (TCS) results from the compromised development of the first and second
pharyngeal arches
The pharyngeal arches, also known as visceral arches'','' are structures seen in the embryonic development of vertebrates that are recognisable precursors for many structures. In fish, the arches are known as the branchial arches, or gill arch ...
during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. TCS is caused by the
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense mu ...
of the
TCOF1 gene, which causes neural crest cells to undergo
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
during
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sper ...
. Although
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
of the TCOF1 gene are among the best characterized in their role in TCS, mutations in
POLR1C and
POLR1D genes
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
have also been linked to the
pathogenesis of TCS.
Cell lineages
Neural crest cells originating from different positions along the
anterior
Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position pr ...
-posterior axis develop into various tissues. These regions of neural crest can be divided into four main functional domains, which include the cranial neural crest, trunk neural crest, vagal and sacral neural crest, and cardiac neural crest.
Cranial neural crest
Cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones.
[Taneyhill, L.A. (2008). "To adhere or not to adhere: the role of Cadherins in neural crest development". Cell Adh Migr. 2, 223–30.] These cells enter the pharyngeal pouches and arches where they contribute to the
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or '' T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invader ...
, bones of the middle ear and jaw and the
odontoblasts of the tooth primordia.
Trunk neural crest
Trunk neural crest gives rise two populations of cells. One group of cells fated to become
melanocytes
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
M ...
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
The adrenal medulla ( la, medulla glandulae suprarenalis) is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cel ...
, 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 and 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
In biology, a septum (Latin for ''something that encloses''; plural septa) is a wall, dividing a cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate.
Examples
Human anatomy
* Interat ...
, which divides the pulmonary circulation from the aorta.
The semilunar valves of the heart are associated with neural crest cells according to new research.
Evolution
Several structures that distinguish the vertebrates from other chordates are formed from the derivatives of neural crest cells. In their "New head" theory, Gans and Northcut argue 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.
However, considering the neural crest a vertebrate innovation does not mean that it arose ''
de novo''. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the
co-option of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context. This idea is supported by
in situ hybridization data that shows the conservation of the neural plate border specifiers in
protochordates, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates.
In some non-vertebrate chordates such as
tunicates a lineage of cells (melanocytes) has been identified, which are similar to neural crest cells in vertebrates. This implies that a rudimentary neural crest existed in a
common ancestor
Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. All living beings are in fact descendants of a unique ancestor commonly referred to as the last universal comm ...
of vertebrates and tunicates.
Neural crest derivatives
Ectomesenchyme (also known as mesectoderm):
odontoblasts,
dental papillae, the
chondrocranium
The chondrocranium (or ''cartilaginous neurocranium'') is the primitive cartilaginous skeletal structure of the fetal skull that grows to envelop the rapidly growing embryonic brain.Salentijn, L. ''Biology of Mineralized Tissues: Prenatal Skull Dev ...
(
nasal capsule,
Meckel's cartilage,
scleral ossicles, quadrate, articular, hyoid and columella),
trachea
The trachea, also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends from the ...
l and
laryngeal cartilage, the
dermatocranium (membranous bones), dorsal fins and the turtle plastron (lower vertebrates),
pericytes and smooth muscle of branchial arteries and veins,
tendons of ocular and masticatory muscles,
connective tissue
Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tissue i ...
of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid)
dermis
The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided ...
and adipose tissue of calvaria, ventral neck and face
Endocrine cells:
chromaffin cell
Chromaffin cells, also called pheochromocytes (or phaeochromocytes), are neuroendocrine cells found mostly in the medulla of the adrenal glands in mammals. These cells serve a variety of functions such as serving as a response to stress, monito ...
s of the adrenal medulla,
glomus cells type I/II.
Peripheral nervous system:
Sensory neurons and glia of the
dorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X),
Rohon-Beard cells, some
Merkel cells in the whisker,
Satellite glial cell
Satellite glial cells, formerly called amphicytes, are glial cells that cover the surface of neuron cell bodies in ganglia of the peripheral nervous system. Thus, they are found in sensory, sympathetic, and parasympathetic ganglia. Both sate ...
s of all autonomic and sensory ganglia,
Schwann cells of all peripheral nerves.
Enteric cells:
Enterochromaffin cells
Enterochromaffin (EC) cells (also known as Kulchitsky cells) are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regu ...
.
Melanocyte
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
s and iris muscle and pigment cells, and even associated with some tumors (such as
melanotic neuroectodermal tumor of infancy).
See also
*
First arch syndrome
*
DGCR2—may control neural crest cell migration
*
List of human cell types derived from the germ layers
References
External links
*
*
Diagramat
University of Michigan
, mottoeng = "Arts, Knowledge, Truth"
, former_names = Catholepistemiad, or University of Michigania (1817–1821)
, budget = $10.3 billion (2021)
, endowment = $17 billion (2021)As o ...
Hox domains in chicks
{{Authority control
Embryology of nervous system
Ectoderm
Chordates
Chordate anatomy
Animal nervous system