Neural crest cells are a temporary group of cells unique to
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
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 t ...
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.
...
,
craniofacial Craniofacial (''cranio-'' combining form meaning head or skull + ''-facial'' combining form referring to the facial structures grossly) is an adjective referring to the parts of the head enclosing the brain and the face.
The term is typically used ...
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 mus ...
,
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 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 ...
s 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. Be ...
, 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 t ...
. 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 neurula.
The process begins when the notochord induces the formati ...
, the borders of the neural plate, also known as the
neural fold
The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with Neurulation#Primary neurulation, primary neurulation, meaning that it ...
s, 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, a ...
. Subsequently, neural crest cells from the roof plate of the neural tube undergo an
epithelial to mesenchymal transition
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 intercell ...
, delaminating from the
neuroepithelium Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or ...
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 taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
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
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 levels of mRNA and proteins which, in turn, determine the fun ...
, 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 func ...
, 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 El ...
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 orig ...
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 cell lineage. The term was coined by Robert P. Bolande in 1974.
After th ...
, 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 one blue eye and one brown eye), a white foreloc ...
, 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 in ...
.
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.
Chimera
Chimera, Chimaera, or Chimaira (Greek for " she-goat") originally referred to:
* Chimera (mythology), a fire-breathing monster of Ancient Lycia said to combine parts from multiple animals
* Mount Chimaera, a fire-spewing region of Lycia or Cilicia ...
s, 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 stu ...
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 levels of mRNA and proteins which, in turn, determine the fun ...
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 E ...
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 Group ...
,
BMPs and
Fgfs
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...
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 t ...
(epidermis) from the neural plate during
neural induction
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...
.
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
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may inclu ...
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 fu ...
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 in the neurulating embryo that flanks and forms simultaneously with the neural tube. The cells of this region give rise to somites, blocks of tissue running ...
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-known ...
'' Msx1 is
necessary and sufficient
In logic and mathematics, necessity and sufficiency are terms used to describe a conditional or implicational relationship between two statements. For example, in the conditional statement: "If then ", is necessary for , because the truth of ...
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
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 ...
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
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase p ...
'' and ''
cadherins
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, ...
'', 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 (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, a ...
.
Delamination
After fusion of the
neural fold
The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with Neurulation#Primary neurulation, primary neurulation, meaning that it ...
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, a ...
, 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
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
.
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 intercellula ...
to
mesenchymal
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
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 proper ...
.
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
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
* Bioc ...
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 fu ...
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 o ...
and
FoxD3.
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
The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with Neurulation#Primary neurulation, primary neurulation, meaning that it ...
.
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 complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...
proteins such as
occludin
Occludin is an enzyme ( EC 1.6) that oxidizes NADH. It was first identified in epithelial cells as a 65 kDa integral plasma-membrane protein localized at the tight junctions. Together with Claudins, and zonula occludens-1 (ZO-1), occludin has bee ...
and
cell adhesion molecule
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s such as
NCAM
Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discover ...
and
N''-''Cadherin.
Dorsally
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 prov ...
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 struct ...
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 Gastro ...
,
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 smal ...
, and
twist
Twist may refer to:
In arts and entertainment Film, television, and stage
* ''Twist'' (2003 film), a 2003 independent film loosely based on Charles Dickens's novel ''Oliver Twist''
* ''Twist'' (2021 film), a 2021 modern rendition of ''Olive ...
.
These factors play a direct role in inducing the
epithelial-mesenchymal transition by reducing expression of
occludin
Occludin is an enzyme ( EC 1.6) that oxidizes NADH. It was first identified in epithelial cells as a 65 kDa integral plasma-membrane protein localized at the tight junctions. Together with Claudins, and zonula occludens-1 (ZO-1), occludin has bee ...
and
N-Cadherin
Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the ''CDH2'' gene. CDH2 has also been designated as CD325 (cluster of differentiation 325).
Cadherin-2 is a transmembrane protein expressed in multipl ...
in addition to promoting
modification
Modification may refer to:
* Modifications of school work for students with special educational needs
* Modifications (genetics), changes in appearance arising from changes in the environment
* Posttranslational modifications, changes to protein ...
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 surf ...
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 ...
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 ba ...
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 stru ...
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
![Migration of Neural Crest Cells (v2)](https://upload.wikimedia.org/wikipedia/commons/0/09/Migration_of_Neural_Crest_Cells_%28v2%29.jpg)
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 colu ...
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 use ...
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 Cell (biology), biological cell that can Cellular differentiation, differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor ...
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. Semaphorins ...
/
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 receptor ...
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 stru ...
, and
contact inhibition In cell biology, contact inhibition refers to two different but closely related phenomena: contact inhibition of locomotion (CIL) and contact inhibition of proliferation (CIP). CIL refers to the avoidance behavior exhibited by fibroblast-like cells ...
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
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
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 kinase ...
, 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 electr ...
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 in ...
. 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 compo ...
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 of vertebrates that are recognisable precursors for many structures. In fish, the arches are known as the branchial arches, or gill arch ...
es. 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 E ...
.
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 ...
. 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 i ...
. 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
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 cell lineage. The term was coined by Robert P. Bolande in 1974.
After th ...
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
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 ...
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 cell lineage. The term was coined by Robert P. Bolande in 1974.
After th ...
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 autosomal dominant disorder of melanocyte development.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews ...
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 la ...
. 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 diffe ...
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 compo ...
-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
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 wh ...
. 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 in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms usu ...
. 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 t ...
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 t ...
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 the trait that determines whether a sexually reproducing animal or plant produces male or female gametes. Male plants and animals produce smaller mobile gametes (spermatozoa, sperm, pollen), while females produce larger ones (ova, oft ...
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 in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms usu ...
(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 ...
. 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
Megacolon is an abnormal dilation of the colon (also called the large intestine). This leads to hypertrophy of the colon. The dilation is often accompanied by a paralysis of the peristaltic movements of the bowel. In more extreme cases, the feces ...
), 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 ...
, 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
Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the ''GDNF'' gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particula ...
,
GFRα
The GDNF family receptor-α (GFRα) proteins are a group of co-receptors which form complexes with GDNF-family ligands (GFLs) to activate RET, the receptor of the GFLs. The GFRα co-receptors include the following:
* GFRα1 – preference for ...
,
EDN3
Endothelin-3 is a protein that in humans is encoded by the ''EDN3'' gene.
The protein encoded by this gene is a member of the endothelin family. Endothelins are endothelium-derived vasoactive peptides involved in a variety of biological functions ...
, and
EDNRB
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the ''EDNRB'' gene.
Function
Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger sys ...
.
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 kinase ...
(RTK), forms a complex with
GDNF
Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the ''GDNF'' gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particula ...
and
GFRα
The GDNF family receptor-α (GFRα) proteins are a group of co-receptors which form complexes with GDNF-family ligands (GFLs) to activate RET, the receptor of the GFLs. The GFRα co-receptors include the following:
* GFRα1 – preference for ...
.
EDN3
Endothelin-3 is a protein that in humans is encoded by the ''EDN3'' gene.
The protein encoded by this gene is a member of the endothelin family. Endothelins are endothelium-derived vasoactive peptides involved in a variety of biological functions ...
and
EDNRB
Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the ''EDNRB'' gene.
Function
Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger sys ...
are then implicated in the same signaling network. When this signaling is disrupted in mice,
aganglionosis
Hirschsprung's disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms us ...
, 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 services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other health c ...
are diagnosed within a continuum of disorders broadly labeled
Fetal Alcohol Spectrum Disorder (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 ...
, as evidenced by characteristic
craniofacial abnormalities
Craniofacial abnormalities are congenital musculoskeletal disorders which primarily affect the cranium and facial bones.
They are associated with the development of the pharyngeal arches. Approximately, 5% of the UK or USA population present wit ...
including short
palpebral fissures
The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. In simple terms, it is the opening between the eyelids. In adult humans, this measures about 10 mm vertically and 30 mm horizontally.
Var ...
, 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 tubercl ...
. 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 (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
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 te ...
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 sper ...
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 Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. 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 in ...
is associated with
deletions or
translocations
In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...
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 cell (biology), 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 ...
. 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 dire ...
or
development
Development or developing may refer to:
Arts
*Development hell, when a project is stuck in development
*Filmmaking, development phase, including finance and budgeting
*Development (music), the process thematic material is reshaped
*Photographi ...
. 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 disease, illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormali ...
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 or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
,
facial defects, and some
neurological
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
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 characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
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 with ...
.
Treacher Collins Syndrome
Treacher Collins Syndrome
Treacher Collins syndrome (TCS) is a genetic disorder characterized by deformities of the ears, eyes, cheekbones, and chin. The degree to which a person is affected, however, may vary from mild to severe. Complications may include breathing prob ...
(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 m ...
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 b ...
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 sperm ...
. 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, mi ...
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 interact with CD3EAP, POLR1E and POLR1D
DNA-directed RNA polymerases I and III subunit ...
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, 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
Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
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 prov ...
-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 invaders. ...
, bones of the middle ear and jaw and the
odontoblasts
In vertebrates, an odontoblast is a cell of neural crest origin that is part of the outer surface of the dental pulp, and whose biological function is dentinogenesis, which is the formation of dentin, the substance beneath the tooth enamel on the ...
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.
...
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 that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide in ...
. 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 do ...
, 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
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 ...
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
* Interatri ...
, 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
Co-option (also co-optation, sometimes spelt coöption or coöptation) has two common meanings.
It may refer to the process of adding members to an elite group at the discretion of members of the body, usually to manage opposition and so maintai ...
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
''In situ'' hybridization (ISH) is a type of hybridization that uses a labeled complementary DNA, RNA or modified nucleic acids strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (''in situ'') or ...
data that shows the conservation of the neural plate border specifiers in
protochordate
A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These five ...
s, 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 tunicate is a marine invertebrate animal, a member of the subphylum Tunicata (). It is part of the Chordata, a phylum which includes all animals with dorsal nerve cords and notochords (including vertebrates). The subphylum was at one time ca ...
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
In vertebrates, an odontoblast is a cell of neural crest origin that is part of the outer surface of the dental pulp, and whose biological function is dentinogenesis, which is the formation of dentin, the substance beneath the tooth enamel on the ...
,
dental papilla
In embryology and prenatal development, the dental papilla is a condensation of ectomesenchymal cells called odontoblasts, seen in histologic sections of a developing tooth. It lies below a cellular aggregation known as the enamel organ. The ...
e, the
chondrocranium
The chondrocranium (or ''cartilaginous neurocranium'') is the primitive cartilage, cartilaginous skeleton, skeletal structure of the fetal skull that grows to envelop the rapidly growing embryonic brain.Salentijn, L. ''Biology of Mineralized Tissue ...
(
nasal capsule,
Meckel's cartilage
In humans, the cartilaginous bar of the mandibular arch is formed by what are known as Meckel's cartilages (right and left) also known as Meckelian cartilages; above this the incus and malleus are developed. Meckel's cartilage arises from the first ...
,
scleral ossicles, quadrate, articular, hyoid and columella),
trachea
The trachea, also known as the windpipe, is a Cartilage, 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 ...
l and
laryngeal cartilage, the
dermatocranium The dermatocranium is the portion of the cranium that is composed of dermal bone, as opposed to the endocranium and splanchnocranium, which are composed of endochondral bone. The dermatocranium comprises the skull roof, the facial skeleton (usuall ...
(membranous bones), dorsal fins and the turtle plastron (lower vertebrates),
pericyte
Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...
s and smooth muscle of branchial arteries and veins,
tendons
A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...
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 tiss ...
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 i ...
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, monitor ...
s of the adrenal medulla,
glomus cell
Glomus cells are the cell type mainly located in the carotid bodies and aortic bodies. Glomus type I cells are peripheral chemoreceptors which sense the oxygen, carbon dioxide and pH levels of the blood. When there is a decrease in the blood's pH ...
s type I/II.
Peripheral nervous system:
Sensory neuron
Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The cell ...
s and glia of 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 do ...
, cephalic ganglia (VII and in part, V, IX, and X),
Rohon-Beard cells, some
Merkel cell
Merkel cells, also known as Merkel-Ranvier cells or tactile epithelial cells, are oval-shaped mechanoreceptors essential for light touch sensation and found in the skin of vertebrates. They are abundant in highly sensitive skin like that of the f ...
s in the whisker,
Satellite glial cell
Satellite glial cells, formerly called amphicytes, are glial cells that cover the surface of neuron Soma (biology), cell bodies in Ganglion, ganglia of the peripheral nervous system. Thus, they are found in Dorsal root ganglion, sensory, Sympath ...
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
Melanotic neuroectodermal tumor of infancy is a very rare oral cavity tumor that is seen in patients usually at or around birth. It must be removed to be cured. Definitions: A rare, biphasic, neuroblastic, and pigmented epithelial neoplasm of cr ...
).
See also
*
First arch syndrome
First arch syndromes are congenital defects caused by a failure of neural crest cells to migrate into the first pharyngeal arch
The pharyngeal arches, also known as visceral arches'','' are structures seen in the embryonic development of verte ...
*
DGCR2
The ''DGCR2'' gene encodes the protein integral membrane protein DGCR2/IDD in humans.
Deletions of the 22q11.2 have been associated with a wide range of developmental defects (notably DiGeorge syndrome, velocardiofacial syndrome, conotruncal ano ...
—may control neural crest cell migration
*
List of human cell types derived from the germ layers
This is a list of cells in humans derived from the three embryonic germ layers – ectoderm, mesoderm, and endoderm.
Cells derived from ectoderm
Surface ectoderm Skin
* Trichocyte
* Keratinocyte
Anterior pituitary
* Gonadotrope
* Corticotro ...
References
External links
*
*
Diagramat
University of Michigan
, mottoeng = "Arts, Knowledge, Truth"
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, 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