Neural crest

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Neural crest_table_infobox_0

Neural crestNeural crest_header_cell_0_0_0
IdentifiersNeural crest_header_cell_0_1_0
MeSHNeural crest_header_cell_0_2_0 Neural crest_cell_0_2_1
TENeural crest_header_cell_0_3_0 Neural crest_cell_0_3_1

Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia. Neural crest_sentence_0

After gastrulation, neural crest cells are specified at the border of the neural plate and the non-neural ectoderm. Neural crest_sentence_1

During neurulation, the borders of the neural plate, also known as the neural folds, converge at the dorsal midline to form the neural tube. Neural crest_sentence_2

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. Neural crest_sentence_3

The emergence of neural crest was important in vertebrate evolution because many of its structural derivatives are defining features of the vertebrate clade. Neural crest_sentence_4

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. Neural crest_sentence_5

Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple cell lineages. Neural crest_sentence_6

Abnormalities in neural crest development cause neurocristopathies, which include conditions such as frontonasal dysplasia, Waardenburg–Shah syndrome, and DiGeorge syndrome. Neural crest_sentence_7

Therefore, defining the mechanisms of neural crest development may reveal key insights into vertebrate evolution and neurocristopathies. Neural crest_sentence_8

History Neural crest_section_0

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. Neural crest_sentence_9

He named the tissue ganglionic crest since its final destination was each lateral side of the neural tube where it differentiated into spinal ganglia. Neural crest_sentence_10

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. Neural crest_sentence_11

Cell labeling techniques advanced the field of neural crest because they allowed researchers to visualize the migration of the tissue throughout the developing embryos. Neural crest_sentence_12

In the 1960s Weston and Chibon utilized radioisotopic labeling of the nucleus with tritiated thymidine in chick and amphibian embryo respectively. Neural crest_sentence_13

However, this method suffers from drawbacks of stability, since every time the labeled cell divides the signal is diluted. Neural crest_sentence_14

Modern cell labeling techniques such as rhodamine-lysinated dextran and the vital dye diI have also been developed to transiently mark neural crest lineages. Neural crest_sentence_15

The quail-chick marking system, devised by Nicole Le Douarin in 1969, was another instrumental technique used to track neural crest cells. Neural crest_sentence_16

Chimeras, generated through transplantation, enabled researchers to distinguish neural crest cells of one species from the surrounding tissue of another species. Neural crest_sentence_17

With this technique, generations of scientists were able to reliably mark and study the ontogeny of neural crest cells. Neural crest_sentence_18

Induction Neural crest_section_1

A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. Neural crest_sentence_19

This gene regulatory network can be subdivided into the following four sub-networks described below. Neural crest_sentence_20

Inductive signals Neural crest_section_2

First, extracellular signaling molecules, secreted from the adjacent epidermis and underlying mesoderm such as Wnts, BMPs and Fgfs separate the non-neural ectoderm (epidermis) from the neural plate during neural induction. Neural crest_sentence_21

Wnt signaling has been demonstrated in neural crest induction in several species through gain-of-function and loss-of-function experiments. Neural crest_sentence_22

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. Neural crest_sentence_23

The current role of BMP in neural crest formation is associated with the induction of the neural plate. Neural crest_sentence_24

BMP antagonists diffusing from the ectoderm generates a gradient of BMP activity. Neural crest_sentence_25

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). Neural crest_sentence_26

Fgf from the paraxial mesoderm has been suggested as a source of neural crest inductive signal. Neural crest_sentence_27

Researchers have demonstrated that the expression of dominate-negative Fgf receptor in ectoderm explants blocks neural crest induction when recombined with paraxial mesoderm. Neural crest_sentence_28

The understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete. Neural crest_sentence_29

Neural plate border specifiers Neural crest_section_3

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. Neural crest_sentence_30

These molecules include Zic factors, Pax3/7, Dlx5, Msx1/2 which may mediate the influence of Wnts, BMPs, and Fgfs. Neural crest_sentence_31

These genes are expressed broadly at the neural plate border region and precede the expression of bona fide neural crest markers. Neural crest_sentence_32

Experimental evidence places these transcription factors upstream of neural crest specifiers. Neural crest_sentence_33

For example, in Xenopus Msx1 is necessary and sufficient for the expression of Slug, Snail, and FoxD3. Neural crest_sentence_34

Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos. Neural crest_sentence_35

Neural crest specifiers Neural crest_section_4

Following the expression of neural plate border specifiers is a collection of genes including Slug/Snail, FoxD3, Sox10, Sox9, AP-2 and c-Myc. Neural crest_sentence_36

This suite of genes, designated here as neural crest specifiers, are activated in emergent neural crest cells. Neural crest_sentence_37

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. Neural crest_sentence_38

Moreover, this model organism was instrumental in the elucidation of the role of the Hedghehog signaling pathway in the specification of the neural crest, with the transcription factor Gli2 playing a key role. Neural crest_sentence_39

Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Neural crest_sentence_40

Twist, a bHLH transcription factor, is required for mesenchyme differentiation of the pharyngeal arch structures. Neural crest_sentence_41

Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells. Neural crest_sentence_42

Neural crest effector genes Neural crest_section_5

Finally, neural crest specifiers turn on the expression of effector genes, which confer certain properties such as migration and multipotency. Neural crest_sentence_43

Two neural crest effectors, Rho GTPases and cadherins, function in delamination by regulating cell morphology and adhesive properties. Neural crest_sentence_44

Sox9 and Sox10 regulate neural crest differentiation by activating many cell-type-specific effectors including Mitf, P0, Cx32, Trp and cKit. Neural crest_sentence_45

Migration Neural crest_section_6

Further information: Collective cell migration Neural crest_sentence_46

The migration of neural crest cells involves a highly coordinated cascade of events that begins with closure of the dorsal neural tube. Neural crest_sentence_47

Delamination Neural crest_section_7

After fusion of the neural fold to create the neural tube, cells originally located in the neural plate border become neural crest cells. Neural crest_sentence_48

For migration to begin, neural crest cells must undergo a process called delamination that involves a full or partial epithelial-mesenchymal transition (EMT). Neural crest_sentence_49

Delamination is defined as the separation of tissue into different populations, in this case neural crest cells separating from the surrounding tissue. Neural crest_sentence_50

Conversely, EMT is a series of events coordinating a change from an epithelial to mesenchymal phenotype. Neural crest_sentence_51

For example, delamination in chick embryos is triggered by a BMP/Wnt cascade that induces the expression of EMT promoting transcription factors such as SNAI2 and FoxD3. Neural crest_sentence_52

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 is not entirely fused, whereas delamination in the chick embryo occurs during fusion of the neural fold. Neural crest_sentence_53

Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells by tight junction proteins such as occludin and cell adhesion molecules such as NCAM and N-Cadherin. Neural crest_sentence_54

Dorsally expressed BMPs initiate delamination by inducing the expression of the zinc finger protein transcription factors snail, slug, and twist. Neural crest_sentence_55

These factors play a direct role in inducing the epithelial-mesenchymal transition by reducing expression of occludin and N-Cadherin in addition to promoting modification of NCAMs with polysialic acid residues to decrease adhesiveness. Neural crest_sentence_56

Neural crest cells also begin expressing proteases capable of degrading cadherins such as ADAM10 and secreting matrix metalloproteinases (MMPs) that degrade the overlying basal lamina of the neural tube to allow neural crest cells to escape. Neural crest_sentence_57

Additionally, neural crest cells begin expressing integrins that associate with extracellular matrix proteins, including collagen, fibronectin, and laminin, during migration. Neural crest_sentence_58

Once the basal lamina becomes permeable the neural crest cells can begin migrating throughout the embryo. Neural crest_sentence_59

Migration Neural crest_section_8

Neural crest cell migration occurs in a rostral to caudal direction without the need of a neuronal scaffold such as along a radial glial cell. Neural crest_sentence_60

For this reason the crest cell migration process is termed “free migration”. Neural crest_sentence_61

Instead of scaffolding on progenitor cells, neural crest migration is the result of repulsive guidance via EphB/EphrinB and semaphorin/neuropilin signaling, interactions with the extracellular matrix, and contact inhibition with one another. Neural crest_sentence_62

While Ephrin and Eph proteins have the capacity to undergo bi-directional signaling, neural crest cell repulsion employs predominantly forward signaling to initiate a response within the receptor bearing neural crest cell. Neural crest_sentence_63

Burgeoning neural crest cells express EphB, a receptor tyrosine kinase, which binds the EphrinB transmembrane ligand expressed in the caudal half of each somite. Neural crest_sentence_64

When these two domains interact it causes receptor tyrosine phosphorylation, activation of rhoGTPases, and eventual cytoskeletal rearrangements within the crest cells inducing them to repel. Neural crest_sentence_65

This phenomenon allows neural crest cells to funnel through the rostral portion of each somite. Neural crest_sentence_66

Semaphorin-neuropilin repulsive signaling works synergistically with EphB signaling to guide neural crest cells down the rostral half of somites in mice. Neural crest_sentence_67

In chick embryos, semaphorin acts in the cephalic region to guide neural crest cells through the pharyngeal arches. Neural crest_sentence_68

On top of repulsive repulsive signaling, neural crest cells express β1and α4 integrins which allows for binding and guided interaction with collagen, laminin, and fibronectin of the extracellular matrix as they travel. Neural crest_sentence_69

Additionally, crest cells have intrinsic contact inhibition with one another while freely invading tissues of different origin such as mesoderm. Neural crest_sentence_70

Neural crest cells that migrate through the rostral half of somites differentiate into sensory and sympathetic neurons of the peripheral nervous system. Neural crest_sentence_71

The other main route neural crest cells take is dorsolaterally between the epidermis and the dermamyotome. Neural crest_sentence_72

Cells migrating through this path differentiate into pigment cells of the dermis. Neural crest_sentence_73

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. Neural crest_sentence_74

Clinical significance Neural crest_section_9

Neurocristopathies result from the abnormal specification, migration, differentiation or death of neural crest cells throughout embryonic development. Neural crest_sentence_75

This group of diseases comprises a wide spectrum of congenital malformations affecting many newborns. Neural crest_sentence_76

Additionally, they arise because of genetic defects affecting the formation of neural crest and because of the action of Teratogens Neural crest_sentence_77

Waardenburg's syndrome Neural crest_section_10

Waardenburg's syndrome is a neurocristopathy that results from defective neural crest cell migration. Neural crest_sentence_78

The condition's main characteristics include piebaldism and congenital deafness. Neural crest_sentence_79

In the case of piebaldism, the colorless skin areas are caused by a total absence of neural crest-derived pigment-producing melanocytes. Neural crest_sentence_80

There are four different types of Waardenburg's syndrome, each with distinct genetic and physiological features. Neural crest_sentence_81

Types I and II are distinguished based on whether or not family members of the affected individual have dystopia canthorum. Neural crest_sentence_82

Type III gives rise to upper limb abnormalities. Neural crest_sentence_83

Lastly, type IV is also known as Waardenburg-Shah syndrome, and afflicted individuals display both Waardenburg's syndrome and Hirschsprung's disease. Neural crest_sentence_84

Types I and III are inherited in an autosomal dominant fashion, while II and IV exhibit an autosomal recessive pattern of inheritance. Neural crest_sentence_85

Overall, Waardenburg's syndrome is rare, with an incidence of ~ 2/100,000 people in the United States. Neural crest_sentence_86

All races and sexes are equally affected. Neural crest_sentence_87

There is no current cure or treatment for Waardenburg's syndrome. Neural crest_sentence_88

Hirschsprung's Disease Neural crest_section_11

Also implicated in defects related to neural crest cell development and migration is Hirschsprung's disease (HD or HSCR), characterized by a lack of innervation in regions of the intestine. Neural crest_sentence_89

This lack of innervation can lead to further physiological abnormalities like an enlarged colon (megacolon), obstruction of the bowels, or even slowed growth. Neural crest_sentence_90

In healthy development, neural crest cells migrate into the gut and form the enteric ganglia. Neural crest_sentence_91

Genes playing a role in the healthy migration of these neural crest cells to the gut include RET, GDNF, GFRα, EDN3, and EDNRB. Neural crest_sentence_92

RET, a receptor tyrosine kinase (RTK), forms a complex with GDNF and GFRα. Neural crest_sentence_93

EDN3 and EDNRB are then implicated in the same signaling network. Neural crest_sentence_94

When this signaling is disrupted in mice, aganglionosis, or the lack of these enteric ganglia occurs. Neural crest_sentence_95

Fetal Alcohol Spectrum Disorder Neural crest_section_12

Prenatal alcohol exposure (PAE) is among the most common causes of developmental defects. Neural crest_sentence_96

Depending on the extent of the exposure and the severity of the resulting abnormalities, patients are diagnosed within a continuum of disorders broadly labeled Fetal Alcohol Spectrum Disorder (FASD). Neural crest_sentence_97

Severe FASD can impair neural crest migration, as evidenced by characteristic craniofacial abnormalities including short palpebral fissures, an elongated upper lip, and a smoothened philtrum. Neural crest_sentence_98

However, due to the promiscuous nature of ethanol binding, the mechanisms by which these abnormalities arise is still unclear. Neural crest_sentence_99

Cell culture explants of neural crest cells as well as in vivo developing zebrafish embryos exposed to ethanol show a decreased number of migratory cells and decreased distances travelled by migrating neural crest cells. Neural crest_sentence_100

The mechanisms behind these changes are not well understood, but evidence suggests PAE can increase apoptosis due to increased cytosolic calcium levels caused by IP3-mediated release of calcium from intracellular stores. Neural crest_sentence_101

It has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increased oxidative stress. Neural crest_sentence_102

Despite these, and other advances much remains to be discovered about how ethanol affects neural crest development. Neural crest_sentence_103

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 appear to be minimally affected. Neural crest_sentence_104

DiGeorge syndrome Neural crest_section_13

DiGeorge syndrome is associated with deletions or translocations of a small segment in the human chromosome 22. Neural crest_sentence_105

This deletion may disrupt rostral neural crest cell migration or development. Neural crest_sentence_106

Some defects observed are linked to the pharyngeal pouch system, which receives contribution from rostral migratory crest cells. Neural crest_sentence_107

The symptoms of DiGeorge syndrome include congenital heart defects, facial defects, and some neurological and learning disabilities. Neural crest_sentence_108

Patients with 22q11 deletions have also been reported to have higher incidence of schizophrenia and bipolar disorder. Neural crest_sentence_109

Treacher Collins Syndrome Neural crest_section_14

Treacher Collins Syndrome (TCS) results from the compromised development of the first and second pharyngeal arches during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. Neural crest_sentence_110

TCS is caused by the missense mutation of the TCOF1 gene, which causes neural crest cells to undergo apoptosis during embryogenesis. Neural crest_sentence_111

Although mutations of the TCOF1 gene are among the best characterized in their role in TCS, mutations in POLR1C and POLR1D genes have also been linked to the pathogenesis of TCS. Neural crest_sentence_112

Cell lineages Neural crest_section_15

Neural crest cells originating from different positions along the anterior-posterior axis develop into various tissues. Neural crest_sentence_113

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. Neural crest_sentence_114

Cranial neural crest Neural crest_section_16

Main article: cranial neural crest Neural crest_sentence_115

Cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones. Neural crest_sentence_116

These cells enter the pharyngeal pouches and arches where they contribute to the thymus, bones of the middle ear and jaw and the odontoblasts of the tooth primordia. Neural crest_sentence_117

Trunk neural crest Neural crest_section_17

Main article: trunk neural crest Neural crest_sentence_118

Trunk neural crest gives rise two populations of cells. Neural crest_sentence_119

One group of cells fated to become melanocytes migrates dorsolaterally into the ectoderm towards the ventral midline. Neural crest_sentence_120

A second group of cells migrates ventrolaterally through the anterior portion of each sclerotome. Neural crest_sentence_121

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. Neural crest_sentence_122

Vagal and sacral neural crest Neural crest_section_18

The vagal and sacral neural crest cells develop into the ganglia of the enteric nervous system and the parasympathetic ganglia. Neural crest_sentence_123

Cardiac neural crest Neural crest_section_19

Main article: cardiac neural crest Neural crest_sentence_124

Cardiac neural crest develops into melanocytes, cartilage, connective tissue and neurons of some pharyngeal arches. Neural crest_sentence_125

Also, this domain gives rise to regions of the heart such as the musculo-connective tissue of the large arteries, and part of the septum, which divides the pulmonary circulation from the aorta. Neural crest_sentence_126

The semilunar valves of the heart are associated with neural crest cells according to new research. Neural crest_sentence_127

Evolution Neural crest_section_20

Several structures that distinguish the vertebrates from other chordates are formed from the derivatives of neural crest cells. Neural crest_sentence_128

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. Neural crest_sentence_129

Furthermore, the appearance of these features was pivotal in vertebrate evolution because it enabled a predatory lifestyle. Neural crest_sentence_130

However, considering the neural crest a vertebrate innovation does not mean that it arose . Neural crest_sentence_131

Instead, new structures often arise through modification of existing developmental regulatory programs. Neural crest_sentence_132

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. Neural crest_sentence_133

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. Neural crest_sentence_134

In some non-vertebrate chordates such as tunicates a lineage of cells (melanocytes) has been identified, which are similar to neural crest cells in vertebrates. Neural crest_sentence_135

This implies that a rudimentary neural crest existed in a common ancestor of vertebrates and tunicates. Neural crest_sentence_136

Neural crest derivatives Neural crest_section_21

Ectomesenchyme (also known as mesectoderm): odontoblasts, dental papillae, 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), pericytes and smooth muscle of branchial arteries and veins, tendons of ocular and masticatory muscles, connective tissue of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid) dermis and adipose tissue of calvaria, ventral neck and face Neural crest_sentence_137

Endocrine cells: chromaffin cells of the adrenal medulla, glomus cells type I/II. Neural crest_sentence_138

Peripheral nervous system: Sensory neurons and glia of the dorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X), Rohon-Beard cells, some Merkel cells in the whisker, Satellite glial cells of all autonomic and sensory ganglia, Schwann cells of all peripheral nerves. Neural crest_sentence_139

Enteric cells: Enterochromaffin cells. Neural crest_sentence_140

Melanocytes and iris muscle and pigment cells, and even associated with some tumors (such as melanotic neuroectodermal tumor of infancy). Neural crest_sentence_141

See also Neural crest_section_22

Neural crest_unordered_list_0

Credits to the contents of this page go to the authors of the corresponding Wikipedia page: crest.