Neural crest
Encyclopedia
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral
and enteric neurons and glia.
After gastrulation
, neural crest cells are specified at the border of the neural plate and the non-neural ectoderm
. During neurulation
, the borders of the neural plate, also known as the neural folds, converge at the dorsal midline to form the neural tube
. Subsequently, neural crest cells from the roof plate of the neural tube undergo an epithelial to mesenchymal transition
, delaminating from the neuroepithelium and migrating through the periphery where they differentiate into varied cell types. The emergence of neural crest was important in vertebrate evolution because many of its structural derivatives are defining features of the vertebrate clade.
Underlying the development of neural crest is a gene regulatory network
, described as a set of interacting signals, transcription factors, and downstream effector genes that confer cell characteristics such as multipotency and migratory capabilities. Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple cell lineages. Abnormalities in neural crest development cause neurocristopathies
, which include conditions such as frontonasal dysplasia
, Waardenburg-Shah syndrome, and DiGeorge syndrome
.
Therefore, defining the mechanisms of neural crest development may reveal key insights into vertebrate evolution and neurocristopathies.
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
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
of neural crest cells.
, BMPs
and Fgfs
separate the non-neural 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 for transcription factors involved in the activation of Wnt-dependent target genes, suggestive of a direct role of Wnt signaling in neural crest specification.
The current role of BMP in neural crest formation is associated with the induction of the neural plate. BMP antagonists diffusing from the ectoderm generates a gradient of BMP activity. In this manner, the neural crest lineage forms from intermediate levels of BMP signaling required for the development of the neural plate (low BMP) and epidermis (high BMP).
Fgf from the paraxial mesoderm
has been suggested as a source of neural crest inductive signal. Researchers have demonstrated that the expression of dominate-negative Fgf receptor in ectoderm explants blocks neural crest induction when recombined with paraxial mesoderm. Our current understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete.
Experimental evidence places these transcription factors upstream of neural crest specifiers. For example, in Xenopus
Msx1 is necessary and sufficient for the expression of Slug, Snail, and FoxD3. Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.
Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, a bHLH transcription factor, is required for mesenchyme differentiation of the pharyngeal arch structures. Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.
and cadherins, function in delamination by regulating cell morphology and adhesive properties. Sox9 and Sox10 regulate neural crest differentiation by activating many cell-type-specific effectors including Mitf, P0, Cx32, Trp and cKit.
, bones of the middle ear and jaw and the odontoblasts of the tooth primordia.
. The cells that stay in the sclerotome form the dorsal root ganglia, whereas those that continue more ventrally form the sympathetic ganglia, adrenal medulla
, and the nerves surrounding the aorta.
, also known as the parasympathetic ganglia.
, which divides the pulmonary circulation from the aorta.
The semilunar valves of the heart are associated with neural crest cells according to new research.
However, considering the neural crest a vertebrate innovation does not mean that it was created de novo
. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the co-option
of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context. This idea is supported by in situ hybridization
data that shows the conservation of the neural plate border specifiers in protochordates, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates.
odontoblasts,
dental papilla
e,
the chondrocranium
(nasal capsule, Meckel's cartilage
, scleral ossicles, quadrate, articular, hyoid and columella), tracheal and laryngeal cartilage,
the dermatocranium (membranous bones), dorsal fins and the turtle plastron (lower vertebrates),
pericyte
s 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
and adipose tissue of calvaria, ventral neck and face
Endocrine Cells:
enterochromaffin
,
parafollicular cell
s of the thyroid,
carotid body
type I/II,
adrenal medulla
Peripheral nervous system:
Sensory neuron
s and glia of the dorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X),
Rohon-Beard cell
s,
Merkel cell
s ,
Satellite glial cells of all autonomic and sensory ganglia,
Schwann
cells of all peripheral nerves
Melanocyte
s and iris pigment cells
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
and enteric neurons and glia.
After gastrulation
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
, neural crest cells are specified at the border of the neural plate and the non-neural ectoderm
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
. During neurulation
Neurulation
Neurulation is the stage of organogenesis in vertebrate embryos, during which the neural tube is transformed into the primitive structures that will later develop into the central nervous system....
, the borders of the neural plate, also known as the neural folds, converge at the dorsal midline to form the neural tube
Neural tube
In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord...
. Subsequently, neural crest cells from the roof plate of the neural tube undergo an epithelial to mesenchymal transition
Epithelial-mesenchymal transition
Epithelial-mesenchymal transition or transformation is a hypothesized program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility...
, delaminating from the neuroepithelium and migrating through the periphery where they differentiate into varied cell types. The emergence of neural crest was important in vertebrate evolution because many of its structural derivatives are defining features of the vertebrate clade.
Underlying the development of neural crest is a gene regulatory network
Gene regulatory network
A gene regulatory network or genetic regulatory network is a collection of DNA segments in a cell whichinteract with each other indirectly and with other substances in the cell, thereby governing the rates at which genes in the network are transcribed into mRNA.In general, each mRNA molecule goes...
, described as a set of interacting signals, transcription factors, and downstream effector genes that confer cell characteristics such as multipotency and migratory capabilities. Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple cell lineages. Abnormalities in neural crest development cause neurocristopathies
Neurocristopathy
Neurocristopathy is a term coined by Robert P. Bolande in 1974, referring to a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest cell lineage....
, which include conditions such as frontonasal dysplasia
Frontonasal dysplasia
Frontonasal dysplasia is a rare anomaly with distinct nasal deformities. Its basic characteristics include hypertelorism, bifid nasal tip, or complete midline splitting of the nose. Other features can include median cleft palate and anterior encephalocele. Inheritance is usually distributive....
, Waardenburg-Shah syndrome, and DiGeorge syndrome
DiGeorge syndrome
22q11.2 deletion syndrome, which has several presentations including DiGeorge syndrome , DiGeorge anomaly, velo-cardio-facial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome, Strong syndrome, congenital thymic aplasia, and thymic hypoplasia is a syndrome caused by the deletion of a...
.
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 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 (genetics)
A chimera or chimaera is a single organism that is composed of two or more different populations of genetically distinct cells that originated from different zygotes involved in sexual reproduction. If the different cells have emerged from the same zygote, the organism is called a mosaic...
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
Ontogeny is the origin and the development of an organism – for example: from the fertilized egg to mature form. It covers in essence, the study of an organism's lifespan...
of neural crest cells.
Induction
A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. This gene-regulatory network can be subdivided into the following four sub-networks described below.Inductive signals
First, extracellular signaling molecules, secreted from the adjacent epidermis and underlying mesoderm such WntsWnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
, BMPs
Bone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
and Fgfs
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
separate the non-neural 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 for transcription factors 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
Paraxial mesoderm is the area of mesoderm that forms just lateral to the neural tube on both sides.It differentiates rostrally into somatomeres and caudally into somites.It gives rise to the somitomeres/somites and mesoderm of the branchial arches....
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. Our current 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
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
Msx1 is necessary and sufficient for the expression of Slug, Snail, and FoxD3. Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.
Neural crest specifiers
Following the expression of neural plate border specifiers is a collection of genes including Slug/Snail, FoxD3, Sox10, Sox9, AP-2 and c-Myc. This suite of genes, designated here as neural crest specifiers, are activated in emergent neural crest cells. At least in Xenopus, every neural crest specifier is necessary and/or sufficient for the expression of all other specifiers, demonstrating the existence of extensive cross-regulation.Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, a bHLH transcription factor, is required for mesenchyme differentiation of the pharyngeal arch structures. Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.
Neural crest effector genes
Finally, neural crest specifiers turn on the expression of effector genes, which confer certain properties such as migration and multipotency. Two neural crest effectors, Rho GTPasesRho family of GTPases
The Rho family of GTPases is a family of small signaling G protein , and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants...
and cadherins, function in delamination by regulating cell morphology and adhesive properties. Sox9 and Sox10 regulate neural crest differentiation by activating many cell-type-specific effectors including Mitf, P0, Cx32, Trp and cKit.
Cell lineages
Neural crest cells originating from different positions along the anterior-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. These cells enter the pharyngeal pouches and arches where they contribute to the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, bones of the middle ear and jaw and the odontoblasts of the tooth primordia.
Trunk neural crest
Trunk neural crest gives rise to two populations of cells. One group of cells fated to become melanocytes migrates dorsolaterally into the ectoderm towards the ventral midline. A second group of cells migrates ventrolaterally through the anterior portion of each sclerotomeSclerotome
A sclerotome is part of a somite, a structure in vertebrate embryonic development. Sclerotomes eventually differentiate into the vertebrae and most of the skull...
. The cells that stay in the sclerotome form the dorsal root ganglia, whereas those that continue more ventrally form the sympathetic ganglia, adrenal medulla
Adrenal medulla
The adrenal medulla 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 cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...
, 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 systemEnteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
, also known as the parasympathetic ganglia.
Cardiac neural crest
Cardiac neural crest develops into melanocytes, cartilage, connective tissue and neurons of some pharyngeal arches. Also, this domain gives rise to regions of the heart such as the musculo-connective tissue of the large arteries, and part of the septumSeptum
In anatomy, a septum is a wall, dividing a cavity or structure into smaller ones.-In human anatomy:...
, 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 Gans and Northcut's "New head" theory they argued that the presence of neural crest was the basis for vertebrate specific features, such as sensory ganglia and cranial skeleton. Furthermore, the appearance of these features was pivotal in vertebrate evolution because it enabled a predatory lifestyle.However, considering the neural crest a vertebrate innovation does not mean that it was created de novo
De novo
In general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the co-option
Exaptation
Exaptation, cooption, and preadaptation are related terms referring to shifts in the function of a trait during evolution. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common in both anatomy and behaviour...
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
In situ hybridization is a type of hybridization that uses a labeled complementary DNA or RNA strand to localize a specific DNA or RNA sequence in a portion or section of tissue , or, if the tissue is small enough , in the entire tissue...
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.
Neural Crest derivatives
Mesectoderm :odontoblasts,
dental papilla
Dental papilla
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 dental papilla appears after 8-10 weeks intra uteral life...
e,
the chondrocranium
Chondrocranium
The chondrocranium is the primitive cartilaginous skeletal structure of the fetal skull that grows to envelop the rapidly growing embryonic brain....
(nasal capsule, Meckel's cartilage
Meckel's cartilage
The cartilaginous bar of the mandibular arch is formed by what are known as Meckel’s cartilages also known as Meckelian cartilages; above this the incus and malleus are developed....
, scleral ossicles, quadrate, articular, hyoid and columella), tracheal and laryngeal cartilage,
the dermatocranium (membranous bones), dorsal fins and the turtle plastron (lower vertebrates),
pericyte
Pericyte
A pericyte is a type of cell found in the central nervous system. These cells play an integral role in the maintenance of the blood brain barrier as well as several other homeostatic and hemostatic functions of the brain. Pericytes are also a key component of the neurovascular unit, which also...
s and smooth muscle of branchial arteries and veins,
tendons of ocular and masticatory muscles,
connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid)
dermis
Dermis
The dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...
and adipose tissue of calvaria, ventral neck and face
Endocrine Cells:
enterochromaffin
Enterochromaffin
Enterochromaffin cells are a type of enteroendocrine cell occurring in the epithelia lining the lumen of the digestive tract and the respiratory tract.-Function:They contain about 90% of the body's store of serotonin ....
,
parafollicular cell
Parafollicular cell
Parafollicular cells are cells in the thyroid that produce and secrete calcitonin. They are located adjacent to the thyroid follicles and reside in the connective tissue. These cells are large and have a pale stain compared with the follicular cells or colloid...
s of the thyroid,
carotid body
Carotid body
The carotid body is a small cluster of chemoreceptors and supporting cells located near the fork of the carotid artery ....
type I/II,
adrenal medulla
Adrenal medulla
The adrenal medulla 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 cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...
Peripheral nervous system:
Sensory neuron
Sensory neuron
Sensory neurons are typically classified as the neurons responsible for converting external stimuli from the environment into internal stimuli. They are activated by sensory input , and send projections into the central nervous system that convey sensory information to the brain or spinal cord...
s and glia of the dorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X),
Rohon-Beard cell
Rohon-Beard cell
Rohona-Beard cells are specialized neurons with mechanoreceptor function occurring at the stage of embryonic development in the dorsal part of the spinal cord in fish and amphibians....
s,
Merkel cell
Merkel cell
Merkel cells or Merkel-Ranvier cells are oval receptor cells found in the skin of vertebrates that have synaptic contacts with somatosensory afferents. They are associated with the sense of light touch discrimination of shapes and textures. They can turn malignant and form the skin tumor known as...
s ,
Satellite glial cells of all autonomic and sensory ganglia,
Schwann
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
cells of all peripheral nerves
Melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s and iris pigment cells
External links
- Diagram at University of MichiganUniversity of MichiganThe University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...
- Hox domains in chicks
