| Neural crest | |
|---|---|
 The formation of neural crest during the process of neurulation. Neural crest is first induced in the region of theneural plate border. Afterneural tube closure, neural crest cells delaminate from the region between the dorsal neural tube and overlyingectoderm and migrate out towards the periphery. | |
| Identifiers | |
| MeSH | D009432 |
| TE | crest_by_E5.0.2.1.0.0.2 E5.0.2.1.0.0.2 |
| FMA | 86666 |
| Anatomical terminology | |
Theneural crest is a ridge-like structure that is formed transiently between theepidermalectoderm andneural plate duringvertebrate development.Neural crest cells originate from this structure through theepithelial-mesenchymal transition, and in turn give rise to a diverse cell lineage—includingmelanocytes,craniofacial cartilage and bone,smooth muscle,dentin,peripheral andenteric neurons,adrenal medulla andglia.[1][2]
Aftergastrulation, the neural crest is specified at the border of theneural plate and the non-neuralectoderm. Duringneurulation, the borders of the neural plate, also known as theneural folds, converge at the dorsal midline to form theneural tube.[3] Subsequently, neural crest cells from the roof plate of the neural tube undergo anepithelial to mesenchymal transition, delaminating from theneuroepithelium and migrating through the periphery, where they differentiate into varied cell types.[1] The emergence of the neural crest was important invertebrate evolution because many of its structural derivatives are defining features of the vertebrateclade.[4]
Underlying the development of the neural crest is agene regulatory network, described as a set of interacting signals,transcription factors, and downstreameffector genes, that confer cell characteristics such as multipotency and migratory capabilities.[5] Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiplecell lineages. Abnormalities in neural crest development causeneurocristopathies, which include conditions such asfrontonasal dysplasia,Waardenburg–Shah syndrome, andDiGeorge syndrome.[1]
Defining the mechanisms of neural crest development may reveal key insights into vertebrate evolution andneurocristopathies.
The neural crest was first described in the chick embryo byWilhelm His Sr. in 1868 as "the cord in between" (Zwischenstrang) because of its origin between the neural plate and non-neural ectoderm.[1] He named the tissue "ganglionic crest," since its final destination was each lateral side of the neural tube, where it differentiated into spinal ganglia.[6] During the first half of the 20th century, the majority of research on the neural crest was done using amphibian embryos which was reviewed by Hörstadius (1950) in a well known monograph.[7]
Cell labeling techniques advanced research into the 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.[6]
The quail-chick marking system, devised by Nicole Le Douarin in 1969, was another instrumental technique used to track neural crest cells.[8][9]Chimeras, generated through transplantation, enabled researchers to distinguish neural crest cells of one species from the surrounding tissue of another species. With this technique, generations of scientists were able to reliably mark and study theontogeny of neural crest cells.
A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. Thisgene regulatory network can be subdivided into the following four sub-networks described below.
First, extracellular signaling molecules, secreted from the adjacentepidermis and underlyingmesoderm such asWnts,BMPs andFgfs separate the non-neuralectoderm (epidermis) from the neural plate duringneural induction.[1][4]
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, thepromoter region of slug (a neural-crest-specific gene) contains abinding site fortranscription factors involved in the activation of Wnt-dependent target genes, suggestive of a direct role of Wnt signaling in neural crest specification.[10]
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).[1]
Fgf from theparaxial 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.[11] The understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete.
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.[4]
Experimental evidence places these transcription factors upstream of neural crest specifiers. For example, inXenopus Msx1 isnecessary and sufficient for the expression of Slug, Snail, and FoxD3.[12] Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.[13]
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.[4] 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.[14]
Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, abHLH transcription factor, is required for mesenchyme differentiation of thepharyngeal arch structures.[15] Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.[16]
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 andcadherins, 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.[4]
The migration of neural crest cells involves a highly coordinated cascade of events that begins with closure of thedorsalneural tube.
After fusion of theneural folds to create theneural tube, cells originally located in theneural plate border become neural crestcells.[17] For migration to begin, neural crest cells must undergo a process called delamination that involves a full or partialepithelial–mesenchymal transition (EMT).[18] Delamination is defined as the separation oftissue into different populations, in this case neural crest cells separating from the surrounding tissue.[19] Conversely, EMT is a series of events coordinating a change from anepithelial tomesenchymalphenotype.[18] For example, delamination inchickembryos is triggered by aBMP/Wntcascade that induces the expression of EMT promotingtranscription factors such asSNAI2 andFOXD3.[19] Although all neural crest cells undergo EMT, the timing of delamination occurs at different stages in different organisms: inXenopus laevis embryos there is a massive delamination that occurs when theneural plate is not entirely fused, whereas delamination in thechick embryo occurs during fusion of theneural fold.[19]
Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells bytight junction proteins such asoccludin andcell adhesion molecules such asNCAM andN-Cadherin.[20]Dorsally expressedBMPs initiate delamination by inducing the expression of thezinc finger protein transcription factorssnail,slug, andtwist.[17] These factors play a direct role in inducing theepithelial-mesenchymal transition by reducing expression ofoccludin andN-Cadherin in addition to promotingmodification ofNCAMs withpolysialic acid residues to decrease adhesiveness.[17][21] Neural crest cells also begin expressingproteases capable of degradingcadherins such asADAM10[22] and secretingmatrix metalloproteinases (MMPs) that degrade the overlyingbasal lamina of the neural tube to allow neural crest cells to escape.[20] Additionally, neural crest cells begin expressingintegrins that associate withextracellular matrix proteins, includingcollagen,fibronectin, andlaminin, during migration.[23] Once the basal lamina becomes permeable, neural crest cells can begin migrating throughout the embryo.
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Neural crest cell migration occurs in arostral tocaudal direction without the need of a neuronalscaffold such as along aradial glial cell. For this reason the crest cell migration process is termed "free migration". Instead of scaffolding onprogenitor cells, neural crest migration is the result of repulsive guidance viaEphB/EphrinB andsemaphorin/neuropilin signaling, interactions with theextracellular matrix, andcontact inhibition with one another.[17] 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 thereceptor bearing neural crest cell.[23] Burgeoning neural crest cells express EphB, areceptor tyrosine kinase, which binds the EphrinB transmembraneligand expressed in the caudal half of eachsomite. When these two domains interact it causes receptor tyrosine phosphorylation, activation ofrhoGTPases, and eventualcytoskeletal rearrangements within the crest cells inducing them to repel. This phenomenon allows neural crest cells to funnel through the rostral portion of each somite.[17]
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 thepharyngeal arches. On top of repulsive repulsive signaling, neural crest cells express β1and α4integrins which allows for binding and guided interaction withcollagen,laminin, andfibronectin 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 asmesoderm.[17] Neural crest cells that migrate through the rostral half of somites differentiate intosensory andsympathetic neurons of theperipheral nervous system. The other main route neural crest cells take isdorsolaterally between theepidermis and thedermamyotome. Cells migrating through this path differentiate intopigment cells of thedermis. Further neural crest celldifferentiation and specification into their final cell type is biased by theirspatiotemporal subjection to morphogenic cues such as BMP, Wnt, FGF,Hox, andNotch.[20]
Neurocristopathies result from the abnormal specification, migration, differentiation or death of neural crest cells throughout embryonic development.[24][25] 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 the neural crest and because of the action ofteratogens.[26]
Waardenburg syndrome is aneurocristopathy that results from defective neural crest cell migration. The condition's main characteristics includepiebaldism andcongenital deafness. In the case of piebaldism, the colorlessskin areas are caused by a total absence of neural crest-derivedpigment-producingmelanocytes.[27] There are four different types of Waardenburg syndrome, each with distinctgenetic and physiological features. Types I and II are distinguished based on whether or not family members of the affected individual havedystopia canthorum.[28] 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 andHirschsprung's disease.[29] Types I and III areinherited in anautosomal dominant fashion,[27] while II and IV exhibit anautosomal recessive pattern of inheritance. Overall, Waardenburg's syndrome is rare, with anincidence of ~ 2/100,000 people in the United States. Allraces andsexes are equally affected.[27] There is no current cure or treatment for Waardenburg's syndrome.
Also implicated in defects related to neural crest cell development andmigration isHirschsprung's disease, characterized by a lack of innervation in regions of theintestine. This lack ofinnervation can lead to furtherphysiological abnormalities like an enlargedcolon (megacolon), obstruction of thebowels, or even slowed growth. In healthy development, neural crest cells migrate into thegut and form theenteric ganglia. Genes playing a role in the healthy migration of these neural crest cells to the gut includeRET,GDNF,GFRα,EDN3, andEDNRB.RET, areceptor tyrosine kinase (RTK), forms a complex withGDNF andGFRα.EDN3 andEDNRB are then implicated in the same signaling network. When this signaling is disrupted in mice,aganglionosis, or the lack of these enteric ganglia occurs.[30]
Fetal alcohol spectrum disorder is among the most common causes ofdevelopmental defects.[31] Depending on the extent of the exposure and the severity of the resulting abnormalities,patients are diagnosed within a continuum of disorders broadly labeled fetal alcohol spectrum disorder (FASD). Severe FASD can impair neural crestmigration, as evidenced by characteristiccraniofacial abnormalities including shortpalpebral fissures, an elongated upper lip, and a smoothenedphiltrum. However, due to the promiscuous nature ofethanolbinding, the mechanisms by which these abnormalities arise is still unclear.Cell cultureexplants of neural crest cells as well asin vivo developingzebrafishembryos exposed to ethanol show a decreased number ofmigratory cells and decreased distances travelled by migrating neural crest cells. The mechanisms behind these changes are not well understood, but evidence suggests prenatal alcohol exposure (PAE) can increaseapoptosis due to increasedcytosoliccalcium levels caused byIP3-mediatedrelease of calcium fromintracellular stores. It has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increasedoxidative stress. 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-derivedpigment cells appear to be minimally affected.[32]
DiGeorge syndrome is associated withdeletions ortranslocations of a small segment in thehumanchromosome 22. This deletion may disrupt rostral neural crestcell migration ordevelopment. Some defects observed are linked to thepharyngeal pouch system, which receives contribution from rostral migratory crest cells. Thesymptoms of DiGeorge syndrome includecongenital heart defects,facial defects, and someneurological andlearning disabilities. Patients with 22q11 deletions have also been reported to have higher incidence ofschizophrenia andbipolar disorder.[33]
Treacher Collins syndrome (TCS) results from the compromised development of the first and secondpharyngeal arches during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. TCS is caused by themissense mutation of theTCOF1 gene, which causes neural crest cells to undergoapoptosis duringembryogenesis. Althoughmutations of the TCOF1 gene are among the best characterized in their role in TCS, mutations inPOLR1C andPOLR1Dgenes have also been linked to thepathogenesis of TCS.[34]
Neural crest cells originating from different positions along theanterior-posterior axis develop into various tissues. These regions of the 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.
The cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones.[21] These cells enter the pharyngeal pouches and arches where they contribute to thethymus, bones of the middle ear and jaw and theodontoblasts of the tooth primordia.[35]
The trunk neural crest gives rise to two populations of cells.[36] One group of cells fated to becomemelanocytes migrates dorsolaterally into the ectoderm towards the ventral midline. A second group of cells migrates ventrolaterally through the anterior portion of eachsclerotome. The cells that stay in the sclerotome form thedorsal root ganglia, whereas those that continue more ventrally form the sympathetic ganglia,adrenal medulla, and the nerves surrounding the aorta.[35]
Vagal and sacral neural crest cells develop into the ganglia of theenteric nervous system and the parasympathetic ganglia.[35]
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 theseptum, which divides the pulmonary circulation from the aorta.[35]The semilunar valves of the heart are associated with neural crest cells according to new research.[37]
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.[38][39]
However, considering the neural crest a vertebrate innovation does not mean that it arosede novo. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by theco-option of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context.[40][41] This idea is supported byin situ hybridization data that shows the conservation of the neural plate border specifiers inprotochordates, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates.[5] In some non-vertebrate chordates such astunicates 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 acommon ancestor of vertebrates and tunicates.[42]
Ectomesenchyme (also known asmesectoderm):[43]odontoblasts,dental papillae, thechondrocranium (nasal capsule,Meckel's cartilage,scleral ossicles, quadrate, articular, hyoid and columella),tracheal andlaryngeal cartilage, thedermatocranium (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
Endocrine cells:chromaffin cells of the adrenal medulla,glomus cells type I/II.
Peripheral nervous system:Sensory neurons and glia of thedorsal root ganglia, cephalic ganglia (VII and in part, V, IX, and X),Rohon-Beard cells, someMerkel cells in the whisker,[44][45]Satellite glial cells of all autonomic and sensory ganglia,Schwann cells of all peripheral nerves.
Enteric cells:Enterochromaffin cells.[46]
Melanocytes, iris muscle and pigment cells, and even associated with some tumors (such asmelanotic neuroectodermal tumor of infancy).
