neural-crest
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Neural crest cells are a temporary group of cells unique to
vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an indiv ...
s that arise from the embryonic
ectoderm The ectoderm is one of the three primary germ layer A germ layer is a primary layer of cell (biology), cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans ( ...

ectoderm
germ layer A germ layer is a primary layer of cells that forms during embryonic development An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any ...
, 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 The ''stratum basale'' (basal layer, sometimes referred to as ''stratum germinativum'') is the deepest layer of the five layers of the ...
,
craniofacial Craniofacial (''cranio-'' combining form meaning head Head Sport GmbH is an American-Austrian manufacturing company Manufacturing is the creation or production Production may be: Economics and business * Production (economics) * Producti ...
cartilage and bone,
smooth muscle Smooth muscle is an involuntary non-striated muscle Striated muscle tissue is a muscle tissue Muscle tissue is a soft tissue that composes muscles in animal bodies, and gives rise to muscles' ability to contract. It is also referred to as myo ...

smooth muscle
,
peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of the computer. The term peripheral device refers to all hardware components that are attached to a computer and are controlled by the co ...
and
enteric neuron The enteric nervous system (ENS) or intrinsic nervous system is one of the main divisions of the autonomic nervous system (ANS) and consists of a mesh-like system of neurons that governs the function of the gastrointestinal tract. It is capable of a ...
s and
glia Glia, also called glial cells (singular ''gliocyte'') or neuroglia, are non-neuron A neuron or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapse In the nervous s ...

glia
. After
gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of Cell (biology), cells) is reorganized into a multilayered structure known as the gastrula. Before gastrulat ...

gastrulation
, 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. Opposite the primitive streak The primitive streak is a structure that forms in the blastula during the early stages of bird, avian, reptile, repti ...
and the non-neural
ectoderm The ectoderm is one of the three primary germ layer A germ layer is a primary layer of cell (biology), cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans ( ...

ectoderm
. During
neurulation Neurulation refers to the folding process in vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is a ...

neurulation
, the borders of the neural plate, also known as the
neural fold The neural fold is a structure that arises during neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neuru ...
s, converge at the dorsal midline to form the
neural tube In the developing chordate A chordate () is an animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that function ...

neural tube
. Subsequently, neural crest cells from the roof plate of the neural tube undergo an
epithelial to mesenchymal transition
epithelial to mesenchymal transition
, delaminating from the
neuroepithelium Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube In the developing chordate A chordate () is an animal Animals (also called Metazoa) are multicellular A multicellular organism is an organis ...
and migrating through the periphery where they differentiate into varied cell types. The emergence of neural crest was important in
vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an indiv ...
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 monophyly, monophyletic – that is, composed of a common ancestor and all its lineage (evolution), lineal descendants - on a phylogenetic tree. R ...

clade
. Underlying the development of neural crest is a
gene regulatory network A gene (or genetic) regulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expression Gene expression is the process by which information from a ...

gene regulatory network
, described as a set of interacting signals,
transcription factors In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...

transcription factors
, 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), ''Effector'' (album), a music album by the Experimental Techno group Download * ''EFFector'', a publ ...
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 lineage Cell lineage denotes the developmental history of a tissue or organ from the fertilized embryo. This is based on the tracking of an organism's cellular ancestry due to the cell divisions and relocation as time progresses, this starts with the origi ...
s. Abnormalities in neural crest development cause
neurocristopathies Neurocristopathy is a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest Neural crest cells are a temporary group of cells unique to vertebrate ...
, which include conditions such as
frontonasal dysplasia Frontonasal dysplasia (FND) is a congenital malformation of the midface. For the diagnosis of FND, a patient should present at least two of the following characteristics: hypertelorism (an increased distance between the eyes), a wide nasal root, ve ...
,
Waardenburg–Shah syndrome Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes (or Heterochromia iridum, one blue eye and one brown ey ...
, 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 Chromosome 22 is one of the 23 pairs of chromosome A chromosome is a long DNA molecule with part or al ...
. 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 In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemi ...
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 A gene (or genetic) regulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expression Gene expression is the process by which information from a ...

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 Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate Vertebrates () comprise all species of animal Animals (also calle ...

epidermis
and underlying
mesoderm The mesoderm is the middle layer of the three germ layer A germ layer is a primary layer of cell (biology), cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoa ...

mesoderm
such as Wnts, BMPs and Fgfs separate the non-neural
ectoderm The ectoderm is one of the three primary germ layer A germ layer is a primary layer of cell (biology), cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans ( ...

ectoderm
(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 Binding may refer to: Computing * Binding, associating a network socket Network and networking may refer to: Arts, entertainment, and media * Network (1976 film), ''Network'' (1976 film), a 1976 American film * Network (2019 film), ''Network'' ...
for
transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...
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 Paraxial mesoderm, also known as presomitic or somitic mesoderm is the area of mesoderm The mesoderm is the middle layer of the three germ layer A germ layer is a primary layer of cells that forms during embryonic development. The three germ ...
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 Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank In biological classification In bi ...

Xenopus
'' Msx1 is
necessary and sufficient In logic Logic is an interdisciplinary field which studies truth and reasoning. Informal logic seeks to characterize Validity (logic), valid arguments informally, for instance by listing varieties of fallacies. Formal logic represents stateme ...
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 transcription factor, is required for mesenchyme differentiation of the
pharyngeal arch The pharyngeal arches, also known as visceral arches'','' are structures seen in the embryonic development An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism that consists of mor ...
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 Rho GTPase may refer to: *Any member of the Rho family of GTPases *The members of the Rho family of GTPases belonging to the ''Rho subclass'' *RHOA, the most-studied member of the ''Rho subclass'' of the Rho family of GTPases {{disambiguation ...
'' and ''
cadherins Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the molecular binding, binding of cells with other cells or with th ...
'', 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 Dorsal (from Latin ''dorsum'' ‘back’) may refer to: * Dorsal (anatomy), an anatomical term of location referring to the back or upper side of an organism or parts of an organism * Dorsal, positioned on top of an aircraft's fuselage * Dorsal co ...
neural tube In the developing chordate A chordate () is an animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that function ...

neural tube
.


Delamination

After fusion of the
neural fold The neural fold is a structure that arises during neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neuru ...
to create the
neural tube In the developing chordate A chordate () is an animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that function ...

neural tube
, cells originally located in the
neural plate The neural plate is a key developmental structure that serves as the basis for the nervous system. Opposite the primitive streak The primitive streak is a structure that forms in the blastula during the early stages of bird, avian, reptile, repti ...
border become neural crest
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
. 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 Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Triphosa haesitata'', a species of geometer moth found in North America * ''Triphosa dubitata'', a species of geometer mot ...
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 is one of the four basic types of animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as ...
to
mesenchymal Mesenchyme () is a type of loosely organised animal embryonic development, embryonic connective tissue of Cell differentiation, undifferentiated cells that gives rise to Blood vessel, blood and Lymph vessel, lymph vessels, bone, and muscle tissue ...

mesenchymal
phenotype In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular inter ...

phenotype
. For example, delamination in
embryo An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms ar ...

embryo
s is triggered by a BMP/ Wnt
cascade Cascade, Cascades or Cascading may refer to: Science and technology Science *Cascade waterfalls, or series of waterfalls * Cascade, the CRISPR-associated complex for antiviral defense (a protein complex) * Cascade (grape), a type of fruit * Bioch ...
that induces the expression of EMT promoting
transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...
s such as
SNAI2 Zinc finger protein SNAI2 is a transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, includ ...
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 In molecular biology Molecular biology is ...
. Although all neural crest cells undergo EMT, the timing of delamination occurs at different stages in different organisms: in 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. Opposite the primitive streak The primitive streak is a structure that forms in the blastula during the early stages of bird, avian, reptile, repti ...
is not entirely fused, whereas delamination in the embryo occurs during fusion of the
neural fold The neural fold is a structure that arises during neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neuru ...
. Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells by
tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens'') are multiprotein junctional complex Cell junctions (or intercellular bridges) are a class of cellular structures consisting of multipro ...
proteins such as
occludin Occludin is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme c ...

occludin
and
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the molecular binding, binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help ce ...
s such as
NCAM Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons A neuron or nerve cell is an electrically excitable cell that communicates with other cells via specialized conne ...
and N''-''Cadherin.
Dorsally Standard anatomical terms of location deal unambiguously with the anatomy Anatomy (Greek ''anatomē'', 'dissection') is the branch of biology concerned with the study of the structure of organism In biology, an organism (from Ancient ...
expressed BMPs initiate delamination by inducing the expression of the
zinc finger A zinc finger is a small protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew ...

zinc finger
protein transcription factors
snail A snail is, in loose terms, a shelled gastropod The gastropods (), commonly known as snails and slugs, belong to a large taxonomic Taxonomy (general) is the practice and science of classification of things or concepts, including the pr ...
,
slug Slug, or land slug, is a common name Common may refer to: Places * Common, a townland in County Tyrone, Northern Ireland * Boston Common Boston Common (also known as the Common) is a central public park in downtown Boston, Massachusetts. ...
, and twist. These factors play a direct role in inducing the epithelial-mesenchymal transition by reducing expression of
occludin Occludin is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme c ...

occludin
and
N-Cadherin N-cadherin, also known as Cadherin-2 (CDH2) or neural cadherin (NCAD) is a protein that in humans is encoded by the ''CDH2'' gene. CDH2 has also been designated as CD325 (cluster of differentiation 325). N-cadherin is a transmembrane domain, trans ...
in addition to promoting
modification Modification may refer to: * Modifications Modification may refer to: * Special education#Modifications, Modifications of school work for students with special educational needs * Modifications (genetics), changes in appearance arising from cha ...
of NCAMs with
polysialic acid Polysialic acid is an unusual posttranslational modification that occurs on neural cell adhesion molecules (NCAM). Polysialic acid is considerably anionic. This strong negative charge gives this modification the ability to change the protein's ...
residues to decrease adhesiveness. Neural crest cells also begin expressing
protease A protease (also called a peptidase or proteinase) is an enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into differe ...

protease
s capable of degrading
cadherin Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the molecular binding, binding of cells with other cells or with th ...
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 a disintegrin and metalloproteinase, ADAM family ...
and secreting matrix metalloproteinases (MMPs) that degrade the overlying
basal lamina The basal lamina is a layer of extracellular matrix In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecu ...

basal lamina
of the neural tube to allow neural crest cells to escape. Additionally, neural crest cells begin expressing
integrin Integrins are transmembrane receptors Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell ...

integrin
s that associate with
extracellular matrix In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
proteins, including
collagen Collagen () is the main structural protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowder ...

collagen
,
fibronectin Fibronectin is a high-molecular weight A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical phenomena a ...

fibronectin
, and
laminin Laminins are high-molecular weight (~400 to ~900 kDa) proteins of the extracellular matrix. They are a major component of the basal lamina (one of the layers of the basement membrane), a protein network foundation for most cells and organs. The l ...
, 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 Rostral may refer to: Anatomy * Rostral (anatomical term), situated toward the oral or nasal region * Rostral bone, in ceratopsian dinosaurs * Rostral organ, of certain fish * Rostral scale, in snakes and scaled reptiles Other uses * Rostral col ...
to
caudal Caudal may refer to: Anatomy * Caudal (anatomical term) (from Latin ''caudum''; tail), used to describe how close something is to the trailing end of an organism * Caudal artery, the portion of the dorsal aorta of a vertebrate that passes into the ...
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 The technical meaning of maintenance involves functional checks, servicing, r ...
such as along a
radial glial cell Radial glial cells, or radial glial progenitor cells (RGPs), are Bipolar neuron, 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 as ...
. 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 The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the smallest units of life, and hence are often referred ...
s, neural crest migration is the result of repulsive guidance via EphB/ EphrinB and
semaphorin Semaphorins are a class of secreted and membrane protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir ...
/
neuropilin Neuropilin is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, ...

neuropilin
signaling, interactions with the
extracellular matrix In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
, and
contact inhibition In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Mo ...
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 bearing neural crest cell. Burgeoning neural crest cells express EphB, a
receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity Affinity may refer to: Commerce, finance and law * Affinity (law) In law and in cultural anthropology Cultural anthropology is a branch of anthropology Anthropology is t ...
, which binds the EphrinB transmembrane
ligand In coordination chemistry A coordination complex consists of a central atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by havi ...
expressed in the caudal half of each
somite The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm Paraxial mesoderm, also known as presomitic or somitic mesoderm is the area of mesoderm In all bilaterian animals, the mesoderm is one o ...

somite
. 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 filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeletal
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 arch The pharyngeal arches, also known as visceral arches'','' are structures seen in the embryonic development An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism that consists of mor ...
es. On top of repulsive repulsive signaling, neural crest cells express β1and α4
integrin Integrins are transmembrane receptors Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell ...

integrin
s which allows for binding and guided interaction with
collagen Collagen () is the main structural protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowder ...

collagen
,
laminin Laminins are high-molecular weight (~400 to ~900 kDa) proteins of the extracellular matrix. They are a major component of the basal lamina (one of the layers of the basement membrane), a protein network foundation for most cells and organs. The l ...
, and
fibronectin Fibronectin is a high-molecular weight A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical phenomena a ...

fibronectin
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 layer A germ layer is a primary layer of cell (biology), cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoa ...

mesoderm
. 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 In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, ...
. 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 Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate Vertebrates () comprise all species of animal Animals (also calle ...

epidermis
and the dermamyotome. Cells migrating through this path differentiate into
pigment cells Melanocytes are melanin-producing neural-crest, neural crest-derived cell (biology), cells located in the bottom layer (the stratum basale) of the skin's epidermis (skin), epidermis, the middle layer of the human eye, eye (the uvea), the inner ea ...
of the
dermis The dermis or corium is a layer of skin between the epidermis (skin), epidermis (with which it makes up the cutis (anatomy), cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from s ...
. Further neural crest cell
differentiation Differentiation may refer to: Business * Differentiation (economics), the process of making a product different from other similar products * Product differentiation, in marketing * Differentiated service, a service that varies with the identity o ...
and specification into their final cell type is biased by their spatiotemporal subjection to morphogenic cues such as BMP, Wnt, FGF, Hox, and .


Clinical significance

Neurocristopathies Neurocristopathy is a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest Neural crest cells are a temporary group of cells unique to vertebrate ...
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

is a
neurocristopathy Neurocristopathy is a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest Neural crest cells are a temporary group of cells unique to vertebrate ...
that results from defective neural crest cell migration. The condition's main characteristics include
piebaldism Piebaldism refers to the absence of mature melanin-forming cells (melanocytes) in certain areas of the skin and hair. It is a rare Mendelian inheritance, autosomal dominant disorder of melanocyte development.James, William; Berger, Timothy; Elston, ...
and
congenital deafness Hearing loss is a partial or total inability to hear Hearing, or auditory perception, is the ability to perceive Sound, sounds by detecting Vibration, vibrations, changes in the pressure of the surrounding medium through time, through a ...
. 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 cuticle, animal coverings, such as the arthropod exoskeleton, have differ ...

skin
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 compound , CH4; is among the simplest organic compou ...
-producing
melanocyte Melanocytes are melanin Melanin (; from el, μέλας ''melas'', "black, dark") is a broad term for a group of natural pigments found in most organisms. Melanin is produced through a multistage chemical process known as melanogenesis, wher ...
s. There are four different types of Waardenburg's syndrome, each with distinct and physiological features. Types I and II are distinguished based on whether or not family members of the affected individual have
dystopia canthorum Telecanthus, or dystopia canthorum, refers to increased distance between the inner corners of the eyelids (medial canthi), while the inter-pupillary distance is normal. This is in contrast to hypertelorism, in which the distance between the whol ...
. 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 Hirschsprung's disease (HD or HSCR) is a birth defect A birth defect, also known as a congenital disorder, is a condition present at birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical con ...
. Types I and III are in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The first ...

autosomal dominant
fashion, while II and IV exhibit an
autosomal recessive In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

autosomal recessive
pattern of inheritance. Overall, Waardenburg's syndrome is rare, with an incidence of ~ 2/100,000 people in the United States. All races and
sex Sex is either of two divisions, typically male Male (♂) is the sex of an organism that produces the gamete known as sperm. A male gamete can fuse with a larger female gamete, or ovum, in the process of fertilization. A male cannot sexual r ...
es 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 Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
is
Hirschsprung's disease Hirschsprung's disease (HD or HSCR) is a birth defect A birth defect, also known as a congenital disorder, is a condition present at birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical con ...
(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 The human digestive system consists of the gastrointestinal tract The gastrointestinal tract, (GI tract, GIT, d ...

intestine
. This lack of
innervation A nerve is an enclosed, cable-like bundle of 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 electro ...

innervation
can lead to further
physiological Physiology (; ) is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in the real world. ...
abnormalities like an enlarged
colon Colon commonly refers to: * Colon (punctuation) (:), a punctuation mark * Major part of large intestine, the final section of the digestive system Colon may also refer to: Places * Colon, Michigan, US * Colon, Nebraska, US * Kowloon, Hong Kong, s ...

colon
(
megacolon Megacolon is an abnormal dilation of the colon (anatomy), colon (also called the large intestine). This leads to hypertrophy of the colon. The dilation is often accompanied by a paralysis of the peristalsis, peristaltic movements of the bowel. In m ...
), obstruction of the
bowels The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system The human digestive system consists of the gastrointestinal tract The gastrointestinal tract, (GI tract, GIT, di ...

bowels
, or even slowed growth. In healthy development, neural crest cells migrate into the gut and form the . Genes playing a role in the healthy migration of these neural crest cells to the gut include RET,
GDNF Glial cell-derived neurotrophic factor (GDNF) is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and ...

GDNF
,
GFRα The GDNF family receptor-α (GFRα) protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery ...
,
EDN3 Endothelin-3 is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, f ...
, and
EDNRB Endothelin receptor type B, also known as ETB is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Si ...
. RET, a
receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity Affinity may refer to: Commerce, finance and law * Affinity (law) In law and in cultural anthropology Cultural anthropology is a branch of anthropology Anthropology is t ...
(RTK), forms a complex with
GDNF Glial cell-derived neurotrophic factor (GDNF) is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and ...

GDNF
and
GFRα The GDNF family receptor-α (GFRα) protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery ...
.
EDN3 Endothelin-3 is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, f ...
and
EDNRB Endothelin receptor type B, also known as ETB is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Si ...
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 A patient is any recipient of health care Healthcare is the maintenance or improvement of health Health, according to the , is "a state of complete physical, and social and not merely the absence of and ".. (2006)''Constitution of the ...
are diagnosed within a continuum of disorders broadly labeled
Fetal Alcohol Spectrum Disorder Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person whose mother drank alcohol In , alcohol is an that carries at least one (−OH) bound to a atom. The term alcohol originally referred to ...
(FASD). Severe FASD can impair neural crest
migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...

migration
, as evidenced by characteristic craniofacial abnormalities including short
palpebral fissures An eyelid is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. The human eyelid ...
, an elongated upper lip, and a smoothened
philtrum The philtrum ( la, philtrum from Ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simp ...

philtrum
. However, due to the promiscuous nature of
ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ (anatomy), ...

ethanol
binding Binding may refer to: Computing * Binding, associating a network socket with a local port number and IP address * Data binding, the technique of connecting two data elements together ** UI data binding, linking a user interface element to an eleme ...
, the mechanisms by which these abnormalities arise is still unclear.
Cell culture Cell culture is the process by which cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse ...

Cell culture
explants of neural crest cells as well as
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
developing
zebrafish The zebrafish (''Danio rerio'') is a freshwater fish are common freshwater fish throughout temperate Eurasia. Freshwater fish are those that spend some or all of their lives in fresh water, such as river A river is a natural flowing wate ...

zebrafish
embryos An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms ar ...
exposed to ethanol show a decreased number of 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 Ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ) ...

apoptosis
due to increased
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a s ...
ic
calcium Calcium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elem ...

calcium
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 Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chem ...
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 Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen ...
. 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, neural crest-derived cell (biology), cells located in the bottom layer (the stratum basale) of the skin's epidermis (skin), epidermis, the middle layer of the human eye, eye (the uvea), the inner ea ...
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 Chromosome 22 is one of the 23 pairs of chromosome A chromosome is a long DNA molecule with part or al ...
is associated with deletions or
translocations In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactio ...
of a small segment in the
human Humans (''Homo sapiens'') are the most abundant and widespread species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A speci ...

human
chromosome 22 Chromosome 22 is one of the 23 pairs of chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by ...

chromosome 22
. This deletion may disrupt rostral neural crest
cell migration Cell migration is a central process in the development and maintenance of multicellular organism A multicellular organism is an organism that consists of more than one cell (biology), cell, in contrast to a unicellular organism. All species of ani ...

cell migration
or
development Development or developing may refer to: Arts *Development hell Development hell, development purgatory, development limbo, or production hell, is a media Media may refer to: Physical means Communication * Media (communication), tool ...
. 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 show ...

symptoms
of DiGeorge syndrome include
congenital heart defects A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart The heart is a muscular MUSCULAR (DS-200B), located in the United Kingdom The United ...
, facial defects, and some
neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia ''-logy'' is a suffix in the English language, used with words originally adapted from Ancient Greek ending in (''-logia''). The earliest English exampl ...
and
learning disabilities Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficult ...
. Patients with 22q11 deletions have also been reported to have higher incidence of
schizophrenia Schizophrenia is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may b ...

schizophrenia
and
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of ...

bipolar disorder
.


Treacher Collins Syndrome

Treacher Collins Syndrome Treacher Collins syndrome (TCS) is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome In the fields of molecular biology Molecular biology is the branch of biology ...
(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 An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biol ...
during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. TCS is caused by the
missense mutation In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions ...
of the
TCOF1 Treacle protein is a protein that in humans is encoded by the ''TCOF1'' gene. This gene encodes a nucleolar protein with an LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream bin ...
gene, which causes neural crest cells to undergo
apoptosis Apoptosis (from Ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ) ...

apoptosis
during
embryogenesis An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms ar ...

embryogenesis
. Although
mutations Image:Darwin Hybrid Tulip Mutation 2014-05-01.jpg, A red tulip exhibiting a partially yellow petal due to a mutation in its genes In biology, a mutation is an alteration in the base sequence, nucleotide sequence of the genome of an organism, vi ...

mutations
of the TCOF1 gene are among the best characterized in their role in TCS, mutations in
POLR1C DNA-directed RNA polymerases I and III subunit RPAC1 is a protein that in humans is encoded by the ''POLR1C'' gene. Interactions POLR1C has been shown to Protein-protein interaction, interact with CD3EAP, POLR1E and POLR1D. References Fu ...
and
POLR1D DNA-directed RNA polymerases I and III subunit RPAC2 is a protein that in humans is encoded by the ''POLR1D'' gene. Interactions POLR1D has been shown to Protein-protein_interaction, interact with POLR1C. References Further reading

* ...
genes In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechani ...
have also been linked to the
pathogenesis Pathogenesis is the process by which a disease A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or system ...

pathogenesis
of TCS.


Cell lineages

Neural crest cells originating from different positions along the
anterior Standard anatomical terms of location deal unambiguously with the anatomy Anatomy (Greek ''anatomē'', 'dissection') is the branch of biology concerned with the study of the structure of organism In biology, an organism (from Ancient ...
-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 Lymphatic system#Structure, lymphoid organ of the immune system. Within the thymus, T cell, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body ad ...

thymus
, bones of the middle ear and jaw and the
odontoblasts In vertebrates, an odontoblast is a cell of neural crest Neural crest cells are a temporary group of cells unique to vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukaryotic ...
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 The ''stratum basale'' (basal layer, sometimes referred to as ''stratum germinativum'') is the deepest layer of the five layers of the ...
migrates dorsolaterally into the ectoderm towards the ventral midline. A second group of cells migrates ventrolaterally through the anterior portion of each
sclerotome The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm Paraxial mesoderm, also known as presomitic or somitic mesoderm is the area of mesoderm In all bilaterian animals, the mesoderm is one o ...
. The cells that stay in the sclerotome form the
dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal ...
, 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 The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldostero ...
, 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 The enteric nervous system (ENS) or intrinsic nervous system is one of the main divisions of the autonomic nervous system The autonomic nervous system (ANS), formerly the vegetative nervous system, is a division of the peripheral 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, 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 ''wikt:de novo, de novo''. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the exaptation, 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 Olfactores, common ancestor of vertebrates and tunicates.


Neural crest derivatives

Ectomesenchyme (also known as mesectoderm):
odontoblasts In vertebrates, an odontoblast is a cell of neural crest Neural crest cells are a temporary group of cells unique to vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukaryotic ...
, dental papillae, the chondrocranium (nasal capsule, Meckel's cartilage, scleral ossicles, quadrate, articular, hyoid and columella), tracheal and larynx, 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 of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid)
dermis The dermis or corium is a layer of skin between the epidermis (skin), epidermis (with which it makes up the cutis (anatomy), cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from s ...
and adipose tissue of calvaria, ventral neck and face Endocrine cells: chromaffin cells 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 cells of all autonomic and sensory ganglia, Schwann cell, Schwann cells of all peripheral nerves. Enteric cells: Enterochromaffin cells. Melanocytes 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

* *
Diagram
at University of Michigan
Hox domains in chicks
{{Authority control Embryology of nervous system Ectoderm Chordates Chordate anatomy Animal nervous system