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Neural crest
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<h2 id="history">History</h2> <p>The neural crest was first described in the chick embryo by <a href="/facts/Wilhelm_His_Sr./KvlMyJEq">Wilhelm His Sr.</a> in 1868 as "the cord in between" (Zwischenstrang) because of its origin between the neural plate and non-neural ectoderm.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> He named the tissue "ganglionic crest," since its final destination was each lateral side of the neural tube, where it differentiated into spinal ganglia.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> 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.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>The quail-chick marking system, devised by Nicole Le Douarin in 1969, was another instrumental technique used to track neural crest cells.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> <a href="/facts/Chimera_(genetics)/xs4NDyLP">Chimeras</a>, 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 <a href="/facts/Ontogeny/ckqaQlL7">ontogeny</a> of neural crest cells. </p> <h2 id="induction">Induction</h2> <p>A molecular cascade of events is involved in establishing the migratory and multipotent characteristics of neural crest cells. This <a href="/facts/Gene_regulatory_network/8e0CYrHz">gene regulatory network</a> can be subdivided into the following four sub-networks described below. </p> <h3>Inductive signals</h3> <p>First, extracellular signaling molecules, secreted from the adjacent <a href="/facts/Epidermis/JvRABubP">epidermis</a> and underlying <a href="/facts/Mesoderm/kf77vcNA">mesoderm</a> such as <a href="/facts/Wnt_signaling_pathway/7wxpKrjy">Wnts</a>, <a href="/facts/Bone_morphogenetic_protein/VpwFr7Ih">BMPs</a> and <a href="/facts/Fibroblast_growth_factor/eC48LP3g">Fgfs</a> separate the non-neural <a href="/facts/Ectoderm/lg5p0jTL">ectoderm</a> (epidermis) from the neural plate during <a href="/facts/Neural_induction/hSjrUxCn">neural induction</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p><p>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 <a href="/facts/Promoter_(genetics)/YDYBzLfg">promoter</a> region of slug (a neural-crest-specific gene) contains a <a href="/facts/Binding_site/gd9r9Rw7">binding site</a> for <a href="/facts/Transcription_factor/wro0DPHe">transcription factors</a> involved in the activation of Wnt-dependent target genes, suggestive of a direct role of Wnt signaling in neural crest specification.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>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).<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>Fgf from the <a href="/facts/Paraxial_mesoderm/gXx8az3q">paraxial mesoderm</a> 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.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> The understanding of the role of BMP, Wnt, and Fgf pathways on neural crest specifier expression remains incomplete. </p> <h3>Neural plate border specifiers</h3> <p>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.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p><p>Experimental evidence places these transcription factors upstream of neural crest specifiers. For example, in <i><a href="/facts/Xenopus/AfAtcsyA">Xenopus</a></i> Msx1 is <a href="/facts/Necessary_and_sufficient/G45aDCY9">necessary and sufficient</a> for the expression of Slug, Snail, and FoxD3.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Furthermore, Pax3 is essential for FoxD3 expression in mouse embryos.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p> <h3>Neural crest specifiers</h3> <p>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.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> 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.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>Outside of the tightly regulated network of neural crest specifiers are two other transcription factors Twist and Id. Twist, a <a href="/facts/BHLH/yqfuWejn">bHLH</a> transcription factor, is required for mesenchyme differentiation of the <a href="/facts/Pharyngeal_arch/12PBkJEN">pharyngeal arch</a> structures.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> Id is a direct target of c-Myc and is known to be important for the maintenance of neural crest stem cells.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <h3>Neural crest effector genes</h3> <p>Finally, neural crest specifiers turn on the expression of effector genes, which confer certain properties such as migration and multipotency. Two neural crest effectors, <i><a href="/facts/Rho_family_of_GTPases/RvAaNbp3">Rho GTPases</a></i> and <i><a href="/facts/Cadherins/0ygo2PRB">cadherins</a></i>, 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.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="migration">Migration</h2> <p class="note">Further information: <a href="/facts/Collective_cell_migration/U29FNp4a">Collective cell migration</a></p> <p>The migration of neural crest cells involves a highly coordinated cascade of events that begins with closure of the <a href="/facts/Anatomical_terms_of_location/IpJ1fq2f">dorsal</a> <a href="/facts/Neural_tube/xv4a9Il7">neural tube</a>. </p> <h3>Delamination</h3> <p>After fusion of the <a href="/facts/Neural_fold/kWQbl7pE">neural folds</a> to create the <a href="/facts/Neural_tube/xv4a9Il7">neural tube</a>, cells originally located in the <a href="/facts/Neural_plate/KxI9wKMl">neural plate</a> border become neural crest <a href="/facts/Cell_(biology)/bLM9UQvy">cells</a>.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> For migration to begin, neural crest cells must undergo a process called delamination that involves a full or partial <a href="/facts/Epithelial%E2%80%93mesenchymal_transition/7fTxEBlb">epithelial–mesenchymal transition</a> (EMT).<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> Delamination is defined as the separation of <a href="/facts/Tissue_(biology)/H7CpML7A">tissue</a> into different populations, in this case neural crest cells separating from the surrounding tissue.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> Conversely, EMT is a series of events coordinating a change from an <a href="/facts/Epithelium/ecKHcHC3">epithelial</a> to <a href="/facts/Mesenchymal_stem_cell/W0jeK2a3">mesenchymal</a> <a href="/facts/Phenotype/vxWXKGLj">phenotype</a>.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> For example, delamination in <a href="/facts/Chicken/RD2eTd83">chick</a> <a href="/facts/Embryo/9QHnLVLN">embryos</a> is triggered by a <a href="/facts/Bone_morphogenetic_protein/VpwFr7Ih">BMP</a>/<a href="/facts/Wnt_signaling_pathway/7wxpKrjy">Wnt</a> <a href="/facts/Signal_transduction/1bs0Me6w">cascade</a> that induces the expression of EMT promoting <a href="/facts/Transcription_factor/wro0DPHe">transcription factors</a> such as <a href="/facts/SNAI2/e5PruCFQ">SNAI2</a> and <a href="/facts/FOXD3/s16ggEyR">FOXD3</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Although all neural crest cells undergo EMT, the timing of delamination occurs at different stages in different organisms: in <a href="/facts/African_clawed_frog/khG1KPrd"><i>Xenopus laevis</i></a> embryos there is a massive delamination that occurs when the <a href="/facts/Neural_plate/KxI9wKMl">neural plate</a> is not entirely fused, whereas delamination in the <a href="/facts/Chicken/RD2eTd83">chick</a> embryo occurs during fusion of the <a href="/facts/Neural_fold/kWQbl7pE">neural fold</a>.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p><p>Prior to delamination, presumptive neural crest cells are initially anchored to neighboring cells by <a href="/facts/Tight_junction/CXxxM5H5">tight junction</a> proteins such as <a href="/facts/Occludin/FK34XS69">occludin</a> and <a href="/facts/Cell_adhesion_molecule/84EkpbAb">cell adhesion molecules</a> such as <a href="/facts/Neural_cell_adhesion_molecule/AQAGclUp">NCAM</a> and <a href="/facts/CDH2/K93GctJB">N<i>-</i>Cadherin</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> <a href="/facts/Anatomical_terms_of_location/IpJ1fq2f">Dorsally</a> expressed <a href="/facts/Bone_morphogenetic_protein/VpwFr7Ih">BMPs</a> initiate delamination by inducing the expression of the <a href="/facts/Zinc_finger/dWrlw4t7">zinc finger</a> protein transcription factors <a href="/facts/SNAI1/wJLEGUuJ">snail</a>, <a href="/facts/SNAI2/e5PruCFQ">slug</a>, and <a href="/facts/Twist_transcription_factor/lTIjHaUq">twist</a>.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> These factors play a direct role in inducing the <a href="/facts/Epithelial%E2%80%93mesenchymal_transition/7fTxEBlb">epithelial-mesenchymal transition</a> by reducing expression of <a href="/facts/Occludin/FK34XS69">occludin</a> and <a href="/facts/CDH2/K93GctJB">N-Cadherin</a> in addition to promoting <a href="/facts/Post-translational_modification/KMUayTIc">modification</a> of <a href="/facts/Neural_cell_adhesion_molecule/AQAGclUp">NCAMs</a> with <a href="/facts/Polysialic_acid/aHTh4U0F">polysialic acid</a> residues to decrease adhesiveness.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> Neural crest cells also begin expressing <a href="/facts/Protease/G1ASdVat">proteases</a> capable of degrading <a href="/facts/Cadherin/0ygo2PRB">cadherins</a> such as <a href="/facts/ADAM10/emptH28c">ADAM10</a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> and secreting <a href="/facts/Matrix_metalloproteinase/PqWv0Qsz">matrix metalloproteinases (MMPs)</a> that degrade the overlying <a href="/facts/Basal_lamina/3WcP2HUJ">basal lamina</a> of the neural tube to allow neural crest cells to escape.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> Additionally, neural crest cells begin expressing <a href="/facts/Integrin/DNYUGbBp">integrins</a> that associate with <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular matrix</a> proteins, including <a href="/facts/Collagen/KsyAb72K">collagen</a>, <a href="/facts/Fibronectin/JrPv8TrU">fibronectin</a>, and <a href="/facts/Laminin/JTn5vrM4">laminin</a>, during migration.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> Once the basal lamina becomes permeable, neural crest cells can begin migrating throughout the embryo. </p> <h3>Migration</h3> <p>Neural crest cell migration occurs in a <a href="/facts/Anatomical_terms_of_location/IpJ1fq2f">rostral</a> to <a href="/facts/Anatomical_terms_of_location/IpJ1fq2f">caudal</a> direction without the need of a neuronal <a href="/facts/Scaffold/matrix_attachment_region/IWe3FtbW">scaffold</a> such as along a <a href="/facts/Radial_glial_cell/Y9mvshLn">radial glial cell</a>. For this reason the crest cell migration process is termed "free migration". Instead of scaffolding on <a href="/facts/Progenitor_cell/qW1KMDC1">progenitor cells</a>, neural crest migration is the result of repulsive guidance via <a href="/facts/EPHB3/oLtx4CvL">EphB</a>/<a href="/facts/Ephrin_receptor/Uhakg9gs">EphrinB</a> and <a href="/facts/SEMA4D/43gyB8m9">semaphorin</a>/<a href="/facts/Neuropilin/uGYHoRcC">neuropilin</a> signaling, interactions with the <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular matrix</a>, and <a href="/facts/Contact_inhibition/2cfQFBPL">contact inhibition</a> with one another.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> 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 <a href="/facts/Receptor_(biochemistry)/tjTAC76a">receptor</a> bearing neural crest cell.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> Burgeoning neural crest cells express EphB, a <a href="/facts/Receptor_tyrosine_kinase/1oNWIdV8">receptor tyrosine kinase</a>, which binds the EphrinB transmembrane <a href="/facts/Ligand_(biochemistry)/44QLL4eU">ligand</a> expressed in the caudal half of each <a href="/facts/Somite/VA2uxrky">somite</a>. When these two domains interact it causes receptor tyrosine phosphorylation, activation of <a href="/facts/Rho_family_of_GTPases/RvAaNbp3">rhoGTPases</a>, and eventual <a href="/facts/Cytoskeleton/1sWlJRX9">cytoskeletal</a> rearrangements within the crest cells inducing them to repel. This phenomenon allows neural crest cells to funnel through the rostral portion of each somite.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> </p><p>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 <a href="/facts/Pharyngeal_arch/12PBkJEN">pharyngeal arches</a>. On top of repulsive repulsive signaling, neural crest cells express β1and α4 <a href="/facts/Integrin/DNYUGbBp">integrins</a> which allows for binding and guided interaction with <a href="/facts/Collagen/KsyAb72K">collagen</a>, <a href="/facts/Laminin/JTn5vrM4">laminin</a>, and <a href="/facts/Fibronectin/JrPv8TrU">fibronectin</a> 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 <a href="/facts/Mesoderm/kf77vcNA">mesoderm</a>.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> Neural crest cells that migrate through the rostral half of somites differentiate into <a href="/facts/Sensory_neuron/EwY1m2bV">sensory</a> and <a href="/facts/Sympathetic_nervous_system/hs8psNRd">sympathetic</a> neurons of the <a href="/facts/Peripheral_nervous_system/KjVpVnHU">peripheral nervous system</a>. The other main route neural crest cells take is <a href="/facts/Anatomical_terms_of_location/IpJ1fq2f">dorsolaterally</a> between the <a href="/facts/Epidermis/JvRABubP">epidermis</a> and the <a href="/facts/Dermatome_(embryology)/VA2uxrky">dermamyotome</a>. Cells migrating through this path differentiate into <a href="/facts/Melanocyte/z8KowoXP">pigment cells</a> of the <a href="/facts/Dermis/WAm7Fd6P">dermis</a>. Further neural crest cell <a href="/facts/Cellular_differentiation/bCVqUG7w">differentiation</a> and specification into their final cell type is biased by their <a href="/facts/Spatiotemporal_gene_expression/aECcLbuu">spatiotemporal</a> subjection to morphogenic cues such as BMP, Wnt, FGF, <a href="/facts/Hox_gene/kP1yVyDY">Hox</a>, and <a href="/facts/Notch_signaling_pathway/5sVkTc0A">Notch</a>.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <p><a href="/facts/Neurocristopathies/ue9hHQwy">Neurocristopathies</a> result from the abnormal specification, migration, differentiation or death of neural crest cells throughout embryonic development.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a><a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> 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 of <a href="/facts/Teratogen/j4BN6lsB">teratogens</a> <a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p> <h3>Waardenburg syndrome</h3> <p><a href="/facts/Waardenburg_syndrome/qYgcC2WV">Waardenburg syndrome</a> is a <a href="/facts/Neurocristopathy/ue9hHQwy">neurocristopathy</a> that results from defective neural crest cell migration. The condition's main characteristics include <a href="/facts/Piebaldism/T99SETXc">piebaldism</a> and <a href="/facts/Congenital_hearing_loss/z6Lhd4br">congenital deafness</a>. In the case of piebaldism, the colorless <a href="/facts/Human_skin/cfRXQwSs">skin</a> areas are caused by a total absence of neural crest-derived <a href="/facts/Biological_pigment/7Lv9jMEd">pigment</a>-producing <a href="/facts/Melanocyte/z8KowoXP">melanocytes</a>.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> There are four different types of Waardenburg syndrome, each with distinct <a href="/facts/Genetics/bu8wne0A">genetic</a> and physiological features. Types I and II are distinguished based on whether or not family members of the affected individual have <a href="/facts/Canthus/gjslkboe">dystopia canthorum</a>.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> 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 <a href="/facts/Hirschsprung%27s_disease/a4ep01yF">Hirschsprung's disease</a>.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> Types I and III are <a href="/facts/Heredity/t0aMmRWx">inherited</a> in an <a href="/facts/Genetic_disorder/hFqt2NLn">autosomal dominant</a> fashion,<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> while II and IV exhibit an <a href="/facts/Genetic_disorder/hFqt2NLn">autosomal recessive</a> pattern of inheritance. Overall, Waardenburg's syndrome is rare, with an <a href="/facts/Incidence_(epidemiology)/2BB3FlBK">incidence</a> of ~ 2/100,000 people in the United States. All <a href="/facts/Race_(human_categorization)/cDPnrdXn">races</a> and <a href="/facts/Sex/ssBol2pP">sexes</a> are equally affected.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> There is no current cure or treatment for Waardenburg's syndrome. </p> <h3>Hirschsprung's disease</h3> <p>Also implicated in defects related to neural crest cell development and <a href="/facts/Cellular_migration/5ySAMquQ">migration</a> is <a href="/facts/Hirschsprung%27s_disease/a4ep01yF">Hirschsprung's disease</a>, characterized by a lack of innervation in regions of the <a href="/facts/Intestine/nK2zwqBS">intestine</a>. This lack of <a href="/facts/Innervation/q7GsAfYV">innervation</a> can lead to further <a href="/facts/Physiological/fh25y2pQ">physiological</a> abnormalities like an enlarged <a href="/facts/Large_intestine/vQtlNBv9">colon</a> (<a href="/facts/Megacolon/udu92mGQ">megacolon</a>), obstruction of the <a href="/facts/Bowels/nK2zwqBS">bowels</a>, or even slowed growth. In healthy development, neural crest cells migrate into the <a href="/facts/Gastrointestinal_tract/nK2zwqBS">gut</a> and form the <a href="/facts/Myenteric_plexus/xFPl40n7">enteric ganglia</a>. Genes playing a role in the healthy migration of these neural crest cells to the gut include <a href="/facts/RET_proto-oncogene/KVAsNxGa">RET</a>, <a href="/facts/GDNF/Xsygvg6y">GDNF</a>, <a href="/facts/GFR%CE%B1/H6s90E0T">GFRα</a>, <a href="/facts/EDN3/7j5vWn1T">EDN3</a>, and <a href="/facts/EDNRB/4GTf9SJj">EDNRB</a>. <a href="/facts/RET_proto-oncogene/KVAsNxGa">RET</a>, a <a href="/facts/Receptor_tyrosine_kinase/1oNWIdV8">receptor tyrosine kinase</a> (RTK), forms a complex with <a href="/facts/GDNF/Xsygvg6y">GDNF</a> and <a href="/facts/GFR%CE%B1/H6s90E0T">GFRα</a>. <a href="/facts/EDN3/7j5vWn1T">EDN3</a> and <a href="/facts/EDNRB/4GTf9SJj">EDNRB</a> are then implicated in the same signaling network. When this signaling is disrupted in mice, <a href="/facts/Aganglionosis/a4ep01yF">aganglionosis</a>, or the lack of these enteric ganglia occurs.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> </p> <h3>Fetal alcohol spectrum disorder</h3> <p><a href="/facts/Fetal_alcohol_spectrum_disorder/FWR4hdf7">Fetal alcohol spectrum disorder</a> is among the most common causes of <a href="/facts/Birth_defect/ESfzQhTx">developmental defects</a>.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> Depending on the extent of the exposure and the severity of the resulting abnormalities, <a href="/facts/Patients/b0SWyyVD">patients</a> are diagnosed within a continuum of disorders broadly labeled fetal alcohol spectrum disorder]] (FASD). Severe FASD can impair neural crest <a href="/facts/Cell_migration/5ySAMquQ">migration</a>, as evidenced by characteristic <a href="/facts/Craniofacial_abnormalities/k91Td2bY">craniofacial abnormalities</a> including short <a href="/facts/Palpebral_fissures/ULxPBnbT">palpebral fissures</a>, an elongated upper lip, and a smoothened <a href="/facts/Philtrum/5UY3DaJ1">philtrum</a>. However, due to the promiscuous nature of <a href="/facts/Ethanol/3lCLfBSP">ethanol</a> <a href="/facts/Molecular_binding/cBnorUC5">binding</a>, the mechanisms by which these abnormalities arise is still unclear. <a href="/facts/Cell_culture/7Qhu13D9">Cell culture</a> <a href="/facts/Explant_culture/fHBIklgP">explants</a> of neural crest cells as well as <a href="/facts/In_vivo/kWcWyl6f">in vivo</a> developing <a href="/facts/Zebrafish/Nxg1F1mG">zebrafish</a> <a href="/facts/Embryos/9QHnLVLN">embryos</a> exposed to ethanol show a decreased number of <a href="/facts/Cell_Migration/5ySAMquQ">migratory cells</a> and decreased distances travelled by migrating neural crest cells. The mechanisms behind these changes are not well understood, but evidence suggests PAE can increase <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a> due to increased <a href="/facts/Cytosol/VyXgygWm">cytosolic</a> <a href="/facts/Calcium/hf252CC0">calcium</a> levels caused by <a href="/facts/Inositol_trisphosphate/TDLGCWuG">IP3</a>-mediated <a href="/facts/Calcium_signalling/2zzv1pm6">release of calcium</a> from <a href="/facts/Intracellular/UEPUhSN8">intracellular</a> stores. It has also been proposed that the decreased viability of ethanol-exposed neural crest cells is caused by increased <a href="/facts/Oxidative_stress/HX7dfUUb">oxidative stress</a>. 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 <a href="/facts/Melanocyte/z8KowoXP">pigment cells</a> appear to be minimally affected.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> </p> <h3>DiGeorge syndrome</h3> <p><a href="/facts/DiGeorge_syndrome/EfP0nK9V">DiGeorge syndrome</a> is associated with <a href="/facts/Deletion_(genetics)/6TRPY0ys">deletions</a> or <a href="/facts/Translocations/MKEwqpQw">translocations</a> of a small segment in the <a href="/facts/Human/rlcTENsr">human</a> <a href="/facts/Chromosome_22/s2e5G3LQ">chromosome 22</a>. This deletion may disrupt rostral neural crest <a href="/facts/Cell_migration/5ySAMquQ">cell migration</a> or <a href="/facts/Human_embryonic_development/JeVmIcT0">development</a>. Some defects observed are linked to the <a href="/facts/Pharyngeal_pouch_(embryology)/8y1eY9IJ">pharyngeal pouch</a> system, which receives contribution from rostral migratory crest cells. The <a href="/facts/Symptoms/BzP6MrTN">symptoms</a> of DiGeorge syndrome include <a href="/facts/Congenital_heart_defects/QsuPPC2Y">congenital heart defects</a>, <a href="/facts/Birth_defects/ESfzQhTx">facial defects</a>, and some <a href="/facts/Neurological/TXYEMSYI">neurological</a> and <a href="/facts/Learning_disabilities/HJoAq92N">learning disabilities</a>. Patients with 22q11 deletions have also been reported to have higher incidence of <a href="/facts/Schizophrenia/FMP4lQ57">schizophrenia</a> and <a href="/facts/Bipolar_disorder/aMDwXbV0">bipolar disorder</a>.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> </p> <h3>Treacher Collins syndrome</h3> <p><a href="/facts/Treacher_Collins_syndrome/3BA43UsW">Treacher Collins syndrome</a> (TCS) results from the compromised development of the first and second <a href="/facts/Pharyngeal_arches/12PBkJEN">pharyngeal arches</a> during the early embryonic stage, which ultimately leads to mid and lower face abnormalities. TCS is caused by the <a href="/facts/Missense_mutation/uKQ9dC22">missense mutation</a> of the <a href="/facts/TCOF1/zVfQ563z">TCOF1</a> gene, which causes neural crest cells to undergo <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a> during <a href="/facts/Embryogenesis/1lFY4EoW">embryogenesis</a>. Although <a href="/facts/Mutations/Ee4NnWbY">mutations</a> of the TCOF1 gene are among the best characterized in their role in TCS, mutations in <a href="/facts/POLR1C/46u0XLL1">POLR1C</a> and <a href="/facts/POLR1D/w5Pc8AeN">POLR1D</a> <a href="/facts/Genes/e1swwPY6">genes</a> have also been linked to the <a href="/facts/Pathogenesis/o9kHHK0U">pathogenesis</a> of TCS.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> </p> <h2 id="cell-lineages">Cell lineages</h2> <p>Neural crest cells originating from different positions along the <a href="/facts/Anterior/IpJ1fq2f">anterior</a>-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. </p> <h3>Cranial neural crest</h3> <p class="note">Main article: <a href="/facts/Cranial_neural_crest/gYLo8MRe">cranial neural crest</a></p> <p>The cranial neural crest migrates dorsolaterally to form the craniofacial mesenchyme that differentiates into various cranial ganglia and craniofacial cartilages and bones.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> These cells enter the pharyngeal pouches and arches where they contribute to the <a href="/facts/Thymus/YYEJu7KA">thymus</a>, bones of the middle ear and jaw and the <a href="/facts/Odontoblasts/jdzBkdAo">odontoblasts</a> of the tooth primordia.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> </p> <h3>Trunk neural crest</h3> <p class="note">Main article: <a href="/facts/Trunk_neural_crest/I2Ro1brz">trunk neural crest</a></p> <p>The trunk neural crest gives rise to two populations of cells.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a> One group of cells fated to become <a href="/facts/Melanocytes/z8KowoXP">melanocytes</a> migrates dorsolaterally into the ectoderm towards the ventral midline. A second group of cells migrates ventrolaterally through the anterior portion of each <a href="/facts/Sclerotome/VA2uxrky">sclerotome</a>. The cells that stay in the sclerotome form the <a href="/facts/Dorsal_root_ganglion/7BGJkVxV">dorsal root ganglia</a>, whereas those that continue more ventrally form the sympathetic ganglia, <a href="/facts/Adrenal_medulla/0j2676vR">adrenal medulla</a>, and the nerves surrounding the aorta.<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> </p> <h3>Vagal and sacral neural crest</h3> <p>Vagal and sacral neural crest cells develop into the ganglia of the <a href="/facts/Enteric_nervous_system/W6U5L9s5">enteric nervous system</a> and the parasympathetic ganglia.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> </p> <h3>Cardiac neural crest</h3> <p class="note">Main article: <a href="/facts/Cardiac_neural_crest/kvaKT2A4">cardiac neural crest</a></p> <p><a href="/facts/Cardiac_neural_crest_cells/kvaKT2A4">Cardiac neural crest</a> 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 <a href="/facts/Septum/lPNxGG9u">septum</a>, which divides the pulmonary circulation from the aorta.<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a> The semilunar valves of the heart are associated with neural crest cells according to new research.<a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a> </p> <h2 id="evolution">Evolution</h2> <p>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.<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a><a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> </p><p>However, considering the neural crest a vertebrate innovation does not mean that it arose <i>de novo</i>. Instead, new structures often arise through modification of existing developmental regulatory programs. For example, regulatory programs may be changed by the <a href="/facts/Exaptation/aK8nu0xE">co-option</a> of new upstream regulators or by the employment of new downstream gene targets, thus placing existing networks in a novel context.<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a><a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a> This idea is supported by <a href="/facts/In_situ_hybridization/RFKJedCS">in situ hybridization</a> data that shows the conservation of the neural plate border specifiers in <a href="/facts/Protochordate/AldL6ARm">protochordates</a>, which suggest that part of the neural crest precursor network was present in a common ancestor to the chordates.<a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a> In some non-vertebrate chordates such as <a href="/facts/Tunicates/9e4penn8">tunicates</a> 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 <a href="/facts/Olfactores/yp73a26I">common ancestor</a> of vertebrates and tunicates.<a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> </p> <h2 id="neural-crest-derivatives">Neural crest derivatives</h2> <p>Ectomesenchyme (also known as mesectoderm):<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a> <a href="/facts/Odontoblasts/jdzBkdAo">odontoblasts</a>, <a href="/facts/Dental_papilla/eHtXc9bJ">dental papillae</a>, the <a href="/facts/Chondrocranium/sT5WEp06">chondrocranium</a> (nasal capsule, <a href="/facts/Meckel%27s_cartilage/jqrK9qnP">Meckel's cartilage</a>, scleral ossicles, quadrate, articular, hyoid and columella), <a href="/facts/Trachea/zMSEwjAy">tracheal</a> and <a href="/facts/Larynx/0bhtXI3Q">laryngeal</a> cartilage, the <a href="/facts/Dermatocranium/le93vUtq">dermatocranium</a> (membranous bones), dorsal fins and the turtle plastron (lower vertebrates), <a href="/facts/Pericyte/2S2Y1vd4">pericytes</a> and smooth muscle of branchial arteries and veins, <a href="/facts/Tendons/M0Kdf7Fy">tendons</a> of ocular and masticatory muscles, <a href="/facts/Connective_tissue/mal3fc7k">connective tissue</a> of head and neck glands (pituitary, salivary, lachrymal, thymus, thyroid) <a href="/facts/Dermis/WAm7Fd6P">dermis</a> and adipose tissue of calvaria, ventral neck and face </p><p>Endocrine cells: <a href="/facts/Chromaffin_cell/ydWmHLLo">chromaffin cells</a> of the adrenal medulla, <a href="/facts/Glomus_cell/xTFK4We2">glomus cells</a> type I/II. </p><p>Peripheral nervous system: <a href="/facts/Sensory_neuron/EwY1m2bV">Sensory neurons</a> and glia of the <a href="/facts/Dorsal_root_ganglia/7BGJkVxV">dorsal root ganglia</a>, cephalic ganglia (VII and in part, V, IX, and X), <a href="/facts/Rohon-Beard_cell/VBRQypTe">Rohon-Beard cells</a>, some <a href="/facts/Merkel_cell/o61p10YA">Merkel cells</a> in the whisker,<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a><a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> <a href="/facts/Satellite_glial_cell/RdsdHE8k">Satellite glial cells</a> of all autonomic and sensory ganglia, <a href="/facts/Schwann_cell/fcdM1444">Schwann</a> cells of all peripheral nerves. </p><p>Enteric cells: <a href="/facts/Enterochromaffin_cells/Wzno95rP">Enterochromaffin cells</a>.<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> </p><p><a href="/facts/Melanocyte/z8KowoXP">Melanocytes</a>, iris muscle and pigment cells, and even associated with some tumors (such as <a href="/facts/Melanotic_neuroectodermal_tumor_of_infancy/vbe7DQxA">melanotic neuroectodermal tumor of infancy</a>). </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/First_arch_syndrome/TQzMshkW">First arch syndrome</a></li> <li><a href="/facts/DGCR2/A1QqJncs">DGCR2</a>—may control neural crest cell migration</li> <li><a href="/facts/List_of_human_cell_types_derived_from_the_germ_layers/5n1hdw80">List of human cell types derived from the germ layers</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="/facts/University_of_New_South_Wales/h64vknzj">Embryology at UNSW</a> <i><a href="https://embryology.med.unsw.edu.au/Notes/ncrest.htm">Notes/ncrest</a></i></li> <li><a href="http://braininfo.rprc.washington.edu/Scripts/ancilcentraldirectory.aspx?ID=445">ancil-445</a> at <a href="/facts/NeuroNames/gPxv6BYH">NeuroNames</a></li> <li><a href="http://www.med.umich.edu/lrc/coursepages/M1/embryology/embryo/images/neural_crest_and_notocord.gif">Diagram</a> at <a href="/facts/University_of_Michigan/6e1Ea5xh">University of Michigan</a></li> <li><a href="https://web.archive.org/web/20070212080444/http://www.palaeos.com/Vertebrates/Bones/Teeth/Images/ChickNeural%20Crest.gif">Hox domains in chicks</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Huang, X.; Saint-Jeannet, J.P. 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