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[[Neural crest cells]] are multipotent cells required for the development of cells, tissues and organ systems.<ref name= "pmid17619792" >{{citeCite journal |vauthors= Snider P, Olaopa M, Firulli AB, Conway SJ |date=2007 |title = Cardiovascular development and the colonizing cardiac neural crest lineage | journal = The Scientific World Journal | volume = 7 | pages = 1090–1113| date = 2007| pmid = 17619792| pmc = 2613651| doi = 10.1100/tsw.2007.189 |pmc=2613651 |pmid=17619792 |doi-access = free}}</ref>
A subpopulation of neural crest cells are the '''cardiac neural crest''' complex. This complex refers to the cells found amongst the midotic placode and somite 3 destined to undergo epithelial-mesenchymal transformation and migration to the heart via [[pharyngeal arches]] 3, 4 and 6.<ref name= "pmid20890117" >{{citeCite journal |vauthors= Kirby ML, Hutson MR |date=2010 title |title= Factors controlling cardiac neural crest cell migration | journal = Cell Adhesion & Migration | volume = 4 | issue = 4 | pages = 609–621 | date = 2010 | pmid = 20890117| pmc = 3011257| doi = 10.4161/cam.4.4.13489 |pmc=3011257 |pmid=20890117}}</ref>
The cardiac neural crest complex plays a vital role in forming connective tissues that aid in outflow septation and modelling of the aortic arch arteries during early development.<ref name= "pmid20890117" /> Ablation of the complex often leads to impaired myocardial functioning similar to symptoms present in [[DiGeorge syndrome]].<ref name= "pmid17224285" >{{citeCite journal |vauthors= Hutson MR, Kirby ML |date=2007 title |title= Model systems for the study of heart development and disease: cardiac neural crest and conotruncal malformations | journal = Seminars in Cell & Developmental Biology | volume = 18 | issue = 1 | pages = 101–110| date = 2007 | pmid = 17224285| pmc = 1858673 | doi = 10.1016/j.semcdb.2006.12.004 |pmc=1858673 |pmid=17224285}}</ref> Consequently, the removal of cardiac crest cells that populate in pharyngeal arches has flow on effects on the [[thymus]], [[parathyroid]] and [[thyroid gland]].<ref name="pmid1185098" >{{citeCite journal |vauthors= Le Lièvre CS, Le Douarin NM |date=1975 title |title= Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos | journal = Development | volume = 34 | issue = 1 | pages = 124–154| date = 1975 | pmid =1185098}}</ref>
[[Neural crest]] cells are a group of temporary, [[Cell potency#Multipotency|multipotent]] (can give rise to some other types of cells but not all) cells that are pinched off during the formation of the [[neural tube]] (precursor to the [[spinal cord]] and brain) and therefore are found at the dorsal (top) region of the neural tube during development.<ref name ="Kirby (1987)">{{Cite journal |last=Kirby M.|first=Margaret [httpL |year=1987 |title=Cardiac Morphogenesis—Recent Research Advances |url=https://www.nature.com/prarticles/journal/v21/n3/pdf/pr198744apr198744.pdf "Cardiac|journal=Pediatric morphogenesis:Research recent|publisher=Springer researchScience advances."]and ''PediatricBusiness Research.''Media 1987LLC |volume=21( |issue=3) 219|pages=219–224 |doi=10.1203/00006450-198703000-00001 224.|pmid=3562119 |issn=0031-3998 |doi-access=free}}</ref> They are derived from the [[ectoderm]] germ layer, but are sometimes called the fourth germ layer because they are so important and give rise to so many other types of cells.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)">{{Cite book |last=Gilbert |first=S. F. [|title=Developmental biology |publisher=Sinauer Associates |year=2010 |isbn=978-0-87893-243-6 |edition=6th |___location=Massachusetts |pages=373–389 |chapter=The Neural Crest |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10065/ "Developmental biology."] Sinauer Associates, Massachusetts, 2010 p373 - 389.}}</ref> They migrate throughout the body and create a large number of differentiated cells such as [[neuron]]s, glial cells, pigment-containing cells in skin, skeletal tissue cells in the head, and many more.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" />
Cardiac neural crest cells (CNCCs) are a type of neural crest cells that migrate to the circumpharyngeal ridge (an arc-shape ridge above the [[pharyngeal arch]]es) and then into the 3rd, 4th and 6th pharyngeal arches and the cardiac outflow tract (OFT).<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)">{{Cite journal |last1=Kuratani S.|first1=Shigeru C. and |last2=Kirby M.|first2=Margaret L. "|date=1992 |title=Migration and distribution of circumpharyngeal crest cells in the chick embryo: formation of the circumpharyngeal ridge and E|url=https:/C8+ crest cells in the vertebrate head region/onlinelibrary." Anatwiley. Reccom/doi/10.1002/ar.1092340213 October|journal=The 1992Anatomical Record |volume=234( |issue=2) p263 - 268 {{PMID|1384396}}pages=263–280 {{doi|doi=10.1002/ar.1092340213 |issn=0003-276X |pmid=1384396|url-access=subscription }}</ref>
They extend from the [[otic placode]]s (the structure in developing embryos that will later form the ears) to the third [[somite]]s (clusters of [[mesoderm]] that will become skeletal muscle, vertebrae and dermis).<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" />
The cardiac neural crest cells have a number of functions including creation of the muscle and [[connective tissue]] walls of large arteries; parts of the cardiac [[septum]]; parts of the [[thyroid]], [[Parathyroid gland|parathyroid]] and [[thymus]] glands. They differentiate into [[melanocytes]] and neurons and the [[cartilage]] and [[connective tissue]] of the pharyngeal arches. They may also contribute to the creation of the carotid body, the organ which monitors oxygen in the blood and regulates breathing.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" />
== Pathway of the migratory cardiac neural crest cell ==
=== Induction ===
[[Neural induction]] is the differentiation of progenitor cells into their final designation or type. The progenitor cells which will become CNCCs are found in the [[epiblast]] about [[Primitive knot|Henson's node]].<ref name="Kuratani (1992)" /><ref name="Kirby (2010)">{{Cite journal |last1=Kirby M.|first1=Margaret KL. and |last2=Hutson M.|first2=Mary R. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011257/pdf/cam0404_0609.pdf|year=2010 "|title=Factors controlling cardiac neural crest cell migration."] |journal=Cell Adhesion and& Migration, December|publisher=Informa 2010,UK Limited |volume=4( |issue=4) p609|pages=609–621 |doi=10.4161/cam.4.4.13489 |issn=1933-6918 621 {{PMC|pmc=3011257}} {{PMID|pmid=20890117 |doi-access=free}}.</ref> Progenitor cells are brought into the [[neural fold]]s. Molecules such as [[Wnt signaling pathway|Wnt]], [[fibroblast growth factor]] (FGF) and [[bone morphogenetic protein]] (BMP) provide [[Recognition signal|signal]]s which induce the progenitor cells to become CNCCs.<ref name="Kuratani (1992)" /><ref name="Kirby (2010)" /> Little is known about the signal cascade that promotes neural crest induction. However, it is known that an intermediate level of BMP is required: if BMP is too high or too low, the cells do not migrate.<ref name="Kirby (2010)" />
=== Initial migration ===
After induction, CNCCs lose their cell to cell contacts. This allows them to move through the [[extracellular matrix]] and interact with its components. The CNCCs, with the assistance of their [[filopodia]] and [[Lamellipodium|lamellipodia]] ([[actin]] containing extensions of [[cytoplasm]] that allow a cell to probe its path of migration), leave the neural tube and migrate along a [[dorsolateral]] pathway to the circumpharyngeal ridge.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)" /> Along this pathway, CNCCs link together to form a stream of migrating cells. Cells at the front of the migration stream have a special [[polygonal]] shape and proliferate at a faster rate than trailing cells.<ref name="Kirby (2010)" />
==Development==
The cardiac neural crest originates from the region of cells between somite 3 and the midotic placode that migrate towards and into the cardiac outflow tract.<ref name= "pmid2197017" >{{citeCite journal |vauthors= Le Lièvre CS, Le Douarin NM |date=1990 title |title= Role of neural crest in congenital heart disease | journal = Circulation | volume =82 82 | issue = 2 | pages = 332–340| date = 1990 | pmid = 2197017| doi = 10.1161/01.CIR.82.2.332 |pmid=2197017 |doi-access = free }}</ref>
The cells migrate from the neural tube to populate pharyngeal arches 3, 4 and 6 with the largest population of the outflow tract originating from those in pharyngeal arches 4.<ref name="pmid20890117" />
From here, a subpopulation of cells will develop into the endothelium of the [[aortic arch]] arteries while others will migrate into the outflow tract to form the aorticopulmonary and truncal septa.<ref name="pmid20890117" /><ref name= "pmid18005956" >{{citeCite journal |vauthors= Bajolle F, Zaffran S, Meilhac SM, Dandonneau M, Chang T, Kelly RG |date=2008 title |title= Myocardium at the base of the aorta and pulmonary trunk is prefigured in the outflow tract of the heart and in subdomains of the second heart field | journal = Developmental Biology | |volume =313 313 | issue = 1 | pages = 25–34| date = 2008 | pmid = 18005956| doi = 10.1016/j.ydbio.2007.09.023 | doi-access pmid= free 18005956}}</ref> Other ectomesenchymal cells will form the thymus and parathyroid glands.<ref name= "pmid6606851" >{{citeCite journal |vauthors= Bockman DE, Kirby ML |date=1984 |title = Dependence of thymus development on derivatives of the neural crest | journal =Science Science| volume =223 223| issue =4635 | pages =498–500 498–500| date bibcode=1984Sci...223..498B 1984| pmid = 6606851| doi = 10.1126/science.6606851 | bibcode pmid= 1984Sci...223..498B 6606851}}</ref>
===Epithelial-mesenchymal transition===
Prior to migration, during a process known as [[epithelial-mesenchymal transition]] (EMT), there is a loss of cell contact, remodelling of the [[cytoskeleton]] and increased motility and interaction with extracellular components in the matrix.<ref name= "pmid8714286" >{{citeCite journal |vauthors= Hay ED |date=1995 |title = An overview of epithelio-mesenchymal trans-formation | journal = Acta Anatomica | volume = 154 | issue = 1 | pages = 8–20| date = 1995 | pmid = 8714286 | doi=10.1159/000147748 |pmid=8714286 }}</ref> An important step in this process is the suppression of adhesion protein [[E-cadherin]] present on [[epithelial cells]] to initiate the migration process. This suppression mechanism occurs via the [[growth factor]] BMP signalling to turn on a transcriptional repressor Smad-interacting protein 1 (Sip1) and marks the beginning of the epithelial-mesenchymal transition.<ref name= "pmid11430829" >{{citeCite journal |vauthors= Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F |date=2007 |title = The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion | journal = Molecular Cell | volume =7 7 | issue =6 6| pages = 1267–1278| date = 2007| pmid = 11430829 | doi = 10.1016/S1097-2765(01)00260-X |pmid=11430829 |doi-access = free}}</ref>
===Early migration===
During migration, crest cells destined for pharyngeal arches maintain contact with each other via [[lamellipodia]] and [[filopodia]]. Short range local contact is maintained with lamellipodia whilst long range non-local contact is maintained with filopodia.<ref name="pmid15548586”">{{citeCite journal |vauthors= Teddy JM, Kulesa PM |date=2004 |title = In vivo evidence for short-and long-range cell communication in cranial neural crest cells | |journal =Development Development| volume =131 131| issue=24 | pages =6141–6151| date = 2004| pmid = 15548586| doi = 10.1242/dev.01534 | doi-access pmid= free15548586}}</ref> During this process, [[connexin 43]] (Cx43) regulates cell interaction by regulating the formation of channels known as [[gap junctions]].<ref name="pmid17619792" /> Impaired Cx43 function in transgenic mice leads to altered coronary artery patterns and abnormal outflow tracts.<ref name= "pmid9640330" >{{citeCite journal |vauthors= Huang GY, Wessels A, Smith BR, Linask KK, Ewart JL, Lo CW |date=1998 |title = Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development | journal = Developmental Biology| |volume =198 198| issue = 1 | pages = 32–44| date = 1998| pmid = 9640330| doi = 10.1006/dbio.1998.8891 |pmid=9640330 |doi-access = free}}</ref> Further gap junction signalling is dependent on a [[cadherin]] mediated cell adhesion formed during cross talking with p120 catenin signalling.<ref name= "pmid11449002" >{{citeCite journal |vauthors= Xu X, Li WE, Huang GY, Meyer R, Chen T, Luo Y, Thomas MP, Radice GL, Lo CW |date=2001 |title = Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions | journal = Journal of Cell Biology | volume = 154 | issue = 1 | pages = 217–230| date = 2001| pmid= 11449002| pmc = 2196865 | doi = 10.1083/jcb.200105047 |pmc=2196865 |pmid=11449002}}</ref>
Appropriate outflow tract formation relies on a [[morphogen]] concentration gradient set up by [[fibroblast growth factor]] (FGF) secreting cells. Cardiac crest cells furthest away from FGF secreting cells will receive lower concentrations of FGF8 signalling than cells closer to FGF secreting cells. This allows for appropriate formation of the outflow tract.<ref name= "pmid12223417" >{{citeCite journal |vauthors= Abu-Issa R, Smyth G, Smoak I, Yamamura K, Meyers EN |date=2002 |title = Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse | journal =Development Development| volume =129 129| issue =19 19 | pages = 4613–4625| date = 2002| doi = 10.1242/dev.129.19.4613 | pmid = 12223417}}</ref> Cells located in rhombomeres 3and 5 undergo programmed cell death under signalling cues from [[semaphorins]]. The lack of cells in this region results in the formation of crest-free zones.<ref name= "pmmid18625214" >{{citeCite journal | vauthors= Toyofuku T, Yoshida J, Sugimoto T, Yamamoto M, Makino N, Takamatsu H, Takegahara N, Suto F, Hori M, Fujisawa H, Kumanogoh A, Kukutani H |date=2007 |title = Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells | |journal = The Scientific World Journal | volume = 7 | issue = 1 | pages = 1090–1113| date = 2007| pmid = 18625214| doi = 10.1016/j.ydbio.2008.06.028 | doi-access pmid= free18625214}}</ref>
The process of migration requires a permissive extracellular matrix.<ref name="pmid20890117" /> The [[enzyme]] [[arginyltransferase]] creates this environment by adding an arginyl group onto newly synthesised proteins during [[post-translational modification]].<ref name= "pmid20300656" >{{citeCite journal | vauthors= Kurosaka S, Leu NA, Zhang F, Bunte R, Saha S, Wang J, Guo C, He W, Kashina A |date=2010 |title = Arginylation-dependent neural crest cell migration is essential for mouse development. | journal = PLOS Genetics | volume =6 6| issue =3 | pages = e1000878| date = 2010| pmid =20300656| pmc = 2837401 | doi = 10.1371/journal.pgen.1000878 |pmc=2837401 |pmid=20300656 |doi-access = free }}</ref> This process aids cells motility and ensures proteins the proteins contained within the actin cytoskeleton is prepped for migration.<ref name="pmid20890117" />
===Circumpharyngeal ridge===
Cell migration towards the circumpharyngeal ridge is forced to paused to allow for the formation of the caudal pharyngeal arches.<ref name="pmid20890117" /> Little is known about this pausing mechanism, but studies conducted in chicks have uncovered the role of [[mesoderm]] expressed factors EphrinB3 and EphrinB4 in forming fibronectin attachments.<ref name= "pmid12117812" >{{citeCite journal |vauthors= Santiago A, Erickson CA |date=2002 |title = Ephrin-B ligands play a dual role in the control of neural crest cell migration | |journal =Development Development| volume =129 129| issue = 15 | pages = 3621–3623| date = 2002| doi = 10.1242/dev.129.15.3621 | pmid = 12117812}}</ref>
===Caudal pharynx and arch artery condensation===
Pharyngeal arches are tissues composed of mesoderm-derived cells enclosed by an external [[ectoderm]] and an internal [[endoderm]].<ref name="pmid20890117" /> Once the caudal pharyngeal arches are formed, cardiac neural crest complexes will migrate towards these and colonise in arches 3, 4 and 6. Cells leading this migration maintain contact with the extracellular matrix and contain filopodia which act as extensions towards the ectodermal pharyngeal arches.<ref name="pmid20890117" /><ref name="pmid15548586”" /> A range of secreted factors ensure appropriate directionality of the cells. FGF8 acts as a chemotactic attraction in directing cellular movement towards pharyngeal arch 4.<ref name="pmid17619792" /><ref name="pmid15548586”" />
A second signalling pathway that directs crest cell movement are the family of endothelin ligands. Migrating cardiac neural crest cells will populate at the correct pharyngeal arches under signalling guidance from EphrinA and Ephrin B variations. This corresponds with receptor expression at the pharyngeal arches. Pharyngeal arch 3 expresses EphrinA and EphrinB1 receptors and pharyngeal arch 2 expresses EphrinB2 and allows for the binding of EphrinA and EphrinB variations to guide migration of the cardiac neural crest cells.<ref name="pmid20890117" />
===Aortic arch remodeling===
The aortic arch arteries transport blood from the [[aorta]] to the head and trunk of the [[embryo]].<ref name= "pmid9558464" >{{citeCite journal |vauthors= Creazzo TL, Godt RE, Leatherbury L, Conway SJ, Kirby ML |date=1998 |title = Role of cardiac neural crest cells in cardiovascular development | journal = Annual Review of Physiology| |volume =60 60| issue = 1 | pages = 267–286| date = 1998| pmid = 9558464| doi = 10.1146/annurev.physiol.60.1.267 |pmid=9558464}}</ref> Normally, early development of the outflow tract begins with a single vessel that forms bilateral symmetrical branches at the aortic sac within pharyngeal arches. This process requires the elongation of the outflow tract as a prerequisite to ensure the correct series of looping and cardiac alignment.<ref name="pmid17619792" /> The cardiac neural crest complex then colonises in the truncal cushion and is localised to the subendothelial layer prior to spiralisation of the endocardial cushion to form the conotruncal ridges. This later undergoes remodelling to form the left-sided aortic pattern present in adult hearts.<ref name="pmid17619792" /> The group of cells found in the third aortic arch gives rise to common [[carotid arteries]]. Cells found in the fourth aortic arch differentiates to form the distal aortic arch and right [[subclavian artery]], whilst cells in the sixth aortic arch develops into the [[pulmonary arteries]]. Cardiac neural crest cells express ''Hox'' genes that supports the development of arteries 3, 4 and 6 and the simultaneous regression of arteries 1 and 2. The ablation of ''Hox'' genes on cardiac neural crest cells causes defective outflow septation.<ref name="pmid9558464" />
==Ablation of cardiac neural crest complex==
===Cardiac outflow anomalies===
One of the main cardiac outflow anomalies present during cardiac neural crest complex ablation is [[persistent truncus arteriosus]].<ref name="pmid2197017" /> This arises when the arterial trunk fails to divide and cause the separation of [[pulmonary artery]] and aorta.<ref name="pmid17619792" /> This results in a lack of aorticopulmonary septum as the vessels which would normally disappear during normal development remains and interrupts the carotid vessels.<ref name="pmid2197017" /> The malformation of the heart and its associated great vessels depends on the extent and ___location of the cardiac neural crest complex ablation.<ref name="pmid2197017" /> Complete removal of cardiac neural crests results in persistent truncus arteriosus characterised in most cases by the presence of just one outflow valve and a ventricular septal defect.<ref name= "pmid10946058" >{{citeCite journal |vauthors= van den Hoff MJ, Moorma AF |date=2000 |title = Cardiac neural crest: the holy grail of cardiac abnormalities? | journal = Cardiovascular Research| |volume =47 47| issue = 2 | pages = 212–216| date = 2000| pmid = 10946058| doi = 10.1016/s0008-6363(00)00127-9 |pmid=10946058 |doi-access = free}}</ref> Mesencephalic neural crest cells interfere with normal development of cardiac outflow septation as its presence leads to persistent truncus arteriosus.<ref name= "pmid2744240" >{{citeCite journal |vauthors= Kirby ML |date=1989 |title = Plasticity and predetermination of mesencephalic and trunk neural crest transplanted into the region of the cardiac neural crest | journal = Developmental Biology| |volume =134 134| issue=2 | pages = 402–412| date = 1989| pmid = 2744240| doi = 10.1016/0012-1606(89)90112-7 |pmid=2744240}}</ref> However, the addition of trunk neural crest cells results in normal heart development.<ref name="pmid2197017" />
Other outcomes of cardiac outflow anomalies includes [[Tetralogy of Fallot]], Eisenmenger's complex, transposition of the great vessels and double outlet right ventricle.<ref name="pmid2197017" />
===Aortic arch arteries anomalies===
[[Overriding aorta]] is caused by the abnormal looping during early development of the heart and is accompanied with ventricular septal defects.<ref name="pmid17224285" /> Instead of abnormal formation of the aorticopulmonary septum, partial removal of cardiac neural crest results in an overriding aorta, whereby the misplacement of the aorta is found over the ventricular [[septum]] as opposed to the left ventricle.<ref name="pmid10946058" /> This results in a reduction of oxygenated blood as the aorta receives some deoxygenated blood from the flow of the [[right ventricle]]. There is a reduction in the quantity of endothelial tubes of [[ectomesenchyme]] in pharyngeal arches that surround the aortic arch arteries.<ref name="pmid2197017" />
Other outcomes of aortic arch artery anomalies includes a double aortic arch, variable absence of the carotid arteries and left aortic arch.<ref name="pmid2197017" />
===Functional changes to the heart===
Functional changes to the heart becomes apparent well before structural changes are observed in the phenotype of ablated chicks. This is due to the embryo compromising morphological changes to the heart to maintain cardiac functioning via [[vasodilation]]. Despite an increase in embryonic [[stroke volume]] and [[cardiac output]], this compensation of decreased contraction results in misalignment of the development vessels due to incomplete looping of the cardiac tube.<ref name="pmid2197017" />
In an adult heart, myocardium contraction occurs via [[excitation-contraction coupling]] whereby cellular [[depolarisation]] occurs and allows an influx of calcium via [[voltage-gated calcium channels]]. A subsequent reuptake of calcium into the [[sarcoplasmic reticulum]] causes a decrease in intracellular calcium to cause myocardium relaxation.<ref name="pmid9558464" /> The removal of the cardiac neural crest complex causes a reduction in contractility of the myocardium. In embryos containing persistent truncus arteriosus, there is a significant 2-fold reduction in calcium currents, thereby interrupting the cardiac excitation-contraction coupling process to cause a reduction in contractility.<ref name="pmid2197017" /><ref name="pmid9558464" />
===Pulmonary venous system===
During [[cardiogenesis]], migration of the cardiac neural crest complex occurs prior to the development of the pulmonary system. There is no visible difference in the pulmonary veins of chick embryos that developed persistent truncus arteriosus and embryos with an intact cardiac neural crest complex. Ablation of the cardiac neural crest complex do not play a role in the systemic or pulmonary venous system as no visible venous defects is observed.<ref name= "pmid2923280" >{{citeCite journal |vauthors= Phillips III MT, Waldo K, Kirby ML |date=1989 |title = Neural crest ablation does not alter pulmonary vein development in the chick embryo. | journal = The Anatomical Record | volume =223 223| issue =3 | pages = 292–298| date = 1989| pmid = 2923280| doi = 10.1002/ar.1092230308 |pmid=2923280 |s2cid = 11552278 }}</ref>
===Derivative development===
Due to its population in pharyngeal arches, removal of the cardiac neural crest complex has flow on effects on the thymus, parathyroid and thyroid gland.<ref name="pmid6606851" />
==Location==
Into the [[pharyngeal arches]] and [[Truncus arteriosus (embryology)]], forming the [[aorticopulmonary septum]]<ref name="pmid10725237">{{citeCite journal |vauthors=Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM |date=April 2000 |title=Fate of the mammalian cardiac neural crest |url=http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=10725237 |journal=Development |volume=127 |issue=8 |pages=1607–16 |date=April 2000 |doi=10.1242/dev.127.8.1607 |pmid=10725237 |url-access=http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=10725237subscription}}</ref> and the [[smooth muscle]] of [[great arteries]].
Anterior of the aorta to become the four [[pre-aortic ganglia]]: ([[celiac ganglion]], [[superior mesenteric ganglion]], [[inferior mesenteric ganglion]] and [[aortical renal ganglia]]).
=== Pause at the circumpharyngeal ridge ===
At the circumpharyngeal arch the CNCCs must pause in their migration while the pharyngeal arches form.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)" /><ref name="Kirby (2010)" />
=== Migration to the pharyngeal arches ===
The CNCCs continue their migration into the newly formed pharyngeal arches, particularly the third, fourth and sixth arches. In the pharyngeal arches the CNCCs assist in the formation of the thyroid and parathyroid glands.<ref name="Kirby (1987)" /><ref name="Gilbert (2010)" /><ref name="Kuratani (1992)" />
The leading cells have long filopodia that assist migration while cells in the middle of the migration have protrusions at their front and back allowing them to interact and communicate with leading cells, trailing cells and receive signals from the extracellular matrix.<ref name="Kirby (2010)" />
A variety of [[growth factor]]s and [[transcription factor]]s in the extracellular matrix signal cells and direct them toward a specific arch.<ref name="Kirby (2010)" /> For example, signalling by [[Fibroblast growth factor|FGF8]] directs CNCCS to the fourth arch and keeps the cells viable.<ref name="Kirby (2010)" />
=== Migration to the cardiac outflow tract ===
{{anchor|Cardiac outflow tract}}The '''cardiac outflow tract''' is a temporary structure in the developing embryo that connects the ventricles with the [[aortic sac]]. Some CNCCs migrate beyond the pharyngeal arches to the cardiac outflow tract.<ref name="Kirby (1987)" /><ref name="Kuratani (1992)" /><ref name="Kirby (2010)" /> CNCCS in the cardiac outflow tract contribute to the formation of the cardiac [[Ganglion|ganglia]] and [[mesenchyme]] at the junction of the [[aorta|subaortic]] and sub pulmonary [[myocardium]] (muscular heart tissue) of the outflow tract.<ref name="Kirby (2010)" /> A smaller portion of the CNCCs migrate to the proximal outflow tract where they help to close the ventricular outflow septum.<ref name="Kirby (1987)" /><ref name="Kuratani (1992)" />
== Molecular pathways ==
Many signaling molecules are required for the differentiation, proliferation, migration and [[apoptosis]] of the CNCCs. The molecular pathways involved include the [[Wnt signaling pathway|Wnt]], [[Notch signaling pathway|Notch]], [[Bone Morphogenetic Protein|BMP]], [[FGF8]] and [[GATA transcription factor|GATA]] families of molecules. In addition to these signaling pathways, these processes are also mediated by environmental factors including blood flow, shear stress, and blood pressure.<ref name="Niessen (2008)" />
The CNCCs interact with the cardiogenic mesoderm cells of the primary and secondary heart fields, which are derived from the cardiac crescent and will give rise to the [[endocardium]], myocardium, and [[epicardium]]. The CNCCs themselves are the precursors to vascular smooth muscle cells and cardiac neurons.<ref name="Brown (2006)">{{Cite book |last1=Brown C|first1=Christopher B. |chapter-url=http://link.springer.com/10.1007/978-0-387-46954-6_8 |title=Neural Crest Induction and Differentiation |last2=Baldwin |first2=H. "Scott |date=2006 |publisher=Springer US |isbn=978-0-387-35136-0 |volume=589 |publication-place=Boston, MA |pages=134–154 |chapter=Neural crestCrest contributionContribution to the cardiovascularCardiovascular system."System |series=Advances in Experimental Medicine 2006,and 589Biology p134 - 154 {{|doi|=10.1007/978-0-387-46954-6_8 |pmid=17076279 }}. Accessed 19 November 2012.</ref>
For example, CNCCs are required for the formation of the [[aorticopulmonary septum]] (APS) that directs cardiac outflow into two tracts: the pulmonary trunk and the aorta of the developing heart. This is an example of [[remodelling]] which is dependent on signalling back and forth between CNCCs and the [[cardiogenic]] [[mesoderm]]. If this signalling is disrupted or there are defects in the CNCCS, cardiovascular anomalies may develop. These anomalies include [[persistent truncus arteriosus]] (PTA), [[double outlet right ventricle]] (DORV), [[tetralogy of Fallot]] and [[DiGeorge syndrome]].<ref name="Pompa (2012)">Pompa{{Cite J.journal L.|last1=de andla Pompa |first1=José Luis |last2=Epstein J.|first2=Jonathan A. "Coordination|date=2012 |title=Coordinating tissueTissue interactionsInteractions: notchNotch signallingSignaling in cardiacCardiac developmentDevelopment and diseaseDisease |url=https://www."cell.com/article/S1534580712000482/pdf |journal=Developmental Cell, February 2012,|volume=22 22(|issue=2) p244 - 264.|pages=244–254 {{|doi|=10.1016/j.devcel.2012.01.014}} Accessed|pmc=3285259 19|pmid=22340493 November 2012.|doi-access=free}}</ref>
=== Wnt ===
Wnt proteins are extracellular [[growth factor]]s that activate intracellular signalling pathways. There are two types of pathways: canonical and non-canonical. The classic canonical Wnt pathway involves [[β-catenin]] protein as a signaling mediator. Wnt maintains β-catenin by preventing against [[Proteasome]] degradation. Thus, β-catenin is stabilized in the presence of Wnt and regulates gene transcription through interaction with TCF/LEF transcription factors.<ref name="Gessert (2010)">Gessert{{Cite S.journal and|last1=Gessert Kuhl|first1=Susanne M.|last2=Kühl [http://circres.ahajournals.org/content/107/2/186.full|first2=Michael "|date=2010-07-23 |title=The multipleMultiple phasesPhases and facesFaces of wntWnt signalingSignaling duringDuring cardiacCardiac differentiationDifferentiation and developmentDevelopment |url=https://www."]ahajournals.org/doi/10.1161/CIRCRESAHA.110.221531 |journal=Circulation Research, 2010 |volume=107( |issue=2) p|pages=186–199 186 - 199 {{doi|doi=10.1161/CIRCRESAHA.110.221531}}. Accessed|pmid=20651295 19|issn=0009-7330|url-access=subscription November 2012.}}</ref> The canonical Wnt/β-catenin pathway is important for control of cell proliferation.<ref name="Kirby (2010)2">{{Cite journal |last1=Kirby M.|first1=Margaret L. and |last2=Hutson M.|first2=Mary R. [https://dx.doi.org/10.4161/cam.4.4.13489|date=2010 "|title=Factors controlling cardiac neural crest cell migration."] |journal=Cell adhesionAdhesion and& migration,Migration December|volume=4 2010|issue=4 |pages=609–621 |doi=10.4161/cam.4(.4).13489 Accessed|issn=1933-6918 20|pmc=3011257 November|pmid=20890117 2012.|doi-access=free}}</ref> The non-canonical Wnt pathway is independent of β-catenin and has an inhibitory effect on canonical Wnt signaling.<ref name="Gessert (2010)" />
Wnt signaling pathways play a role in CNCC development as well as OFT development.<ref name="Gessert (2010)" /> In mice, decrease of β-catenin results in a decrease in the proliferation of CNCCs.<ref name="Gessert (2010)" /> Downregulation of the Wnt coreceptor [[Lrp6]] leads to a reduction of CNCCs in the dorsal neural tube and in the pharyngeal arches, and results in ventricular, septal, and OFT defects.<ref name="Gessert (2010)" /> Canonical Wnt signaling is especially important for cell cycle regulation of CNCC development and the initiation of CNCC migration.<ref name="Gessert (2010)" /> Non-canonical Wnt signaling plays a greater role in promoting cardiac differentiation and OFT development.<ref name="Gessert (2010)" />
=== Notch ===
[[Notch proteins|Notch]] is a transmembrane protein whose signaling is required for differentiation of CNCCs to vascular [[smooth muscle]] cells and for proliferation of cardiac [[myocytes]] (muscle cells of the heart). In mice, disruption of Notch signaling results in aortic arch branching defects and pulmonary stenosis, as well as a defect in the development of the smooth muscle cells of the sixth aortic arch artery, which is the precursor to the pulmonary artery.<ref name="Niessen (2008)">Niessen{{Cite K.journal and|last1=Niessen |first1=Kyle |last2=Karsan A.|first2=Aly "|date=2008-05-23 |title=Notch signalingSignaling in cardiacCardiac development."Development |journal=Circulation Research 2008, |volume=102 p1169|issue=10 - 1181|pages=1169–1181 {{doi|doi=10.1161/CIRCRESAHA.108.174318}} {{PMID|issn=0009-7330 |pmid=18497317 |doi-access=free}}. Accessed 20 November 2012.</ref> In humans, mutations in Notch most often result in bicuspid aortic valve disease and calcification of the aortic valve.<ref name="Garg (2005)">{{Cite journal |last1=Garg V|first1=Vidu |last2=Muth |first2=Alecia N. et|last3=Ransom al|first3=Joshua [http://wwwF.nature |last4=Schluterman |first4=Marie K.com/nature/journal/v437/n7056/full/nature03940 |last5=Barnes |first5=Robert |last6=King |first6=Isabelle N.html "|last7=Grossfeld |first7=Paul D. |last8=Srivastava |first8=Deepak |date=2005-07-17 |title=Mutations in NOTCH1 cause aortic valve disease."] |journal=Nature September|publisher=Springer 2005Science 437(7056)and pBusiness 270Media -LLC 274.|volume=437 {{doi|issue=7056 |pages=270–274 |doi=10.1038/nature03940}} Accessed 20|pmid=16025100 November 2012|bibcode=2005Natur.437..270G |issn=0028-0836}}</ref>
=== Bone morphogenetic proteins ===
[[Bone morphogenetic protein]]s (BMPs) are required for neural crest cell migration into the cardiac cushions (precursors to heart valves and septa) and for differentiation of neural crest cells to smooth muscle cells of the aortic arch arteries. In neural crest–specific Alk2-deficient embryos, the cardiac cushions of the outflow tract are deficient in cells because of defects in neural crest cell migration.<ref name="Kaartinen (2004)">{{Cite journal |last1=Kaartinen V.|first1=Vesa et|last2=Dudas al|first2=Marek "|last3=Nagy |first3=Andre |last4=Sridurongrit |first4=Somyoth |last5=Lu |first5=Min Min |last6=Epstein |first6=Jonathan A. |date=2004-07-15 |title=Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells" |url=https://journals.biologists.com/dev/article/131/14/3481/52362/Cardiac-outflow-tract-defects-in-mice-lacking-ALK2 |journal=Development July 2004,|volume=131 131(|issue=14) p3481 - 3490 {{PMID|15226263}}pages=3481–3490 {{|doi|=10.1242/dev.01214}} Accessed|issn=1477-9129 19|pmid=15226263|url-access=subscription November 2012.}}</ref>
=== Fibroblast growth factor 8 ===
[[Fibroblast growth factor 8]] (FGF8) transcription factors are essential for regulating the addition of secondary heart field cells into the cardiac outflow tract. FGF8 mouse mutants have a range of cardiac defects including underdeveloped arch arteries and transposition of the great arteries.<ref name="Abu-Issa (2002)">{{Cite journal |last1=Abu-Issa R.|first1=Radwan et|last2=Smyth al|first2=Graham [http://dev|last3=Smoak |first3=Ida |last4=Yamamura |first4=Ken-ichi |last5=Meyers |first5=Erik N.biologists.org/content/129/19/4613.full.pdf+html "FGF8|date=2002-10-01 |title=Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse |url=https://journals."]biologists.com/dev/article/129/19/4613/20179/Fgf8-is-required-for-pharyngeal-arch-and |journal=Development October|volume=129 2012|issue=19 |pages=4613–4625 |doi=10.1242/dev.129(.19).4613 p4163|pmid=12223417 |issn=1477-9129|url-access=subscription 4625 Accessed 19 November 2012.}}</ref><ref name= "Frank (2002)" >{{Cite journal |last1=Frank D.|first1=Deborah U. et|last2=Fotheringham al|first2=Lori "FGF8K. |last3=Brewer |first3=Judson A. |last4=Muglia |first4=Louis J. |last5=Tristani-Firouzi |first5=Martin |last6=Capecchi |first6=Mario R. |last7=Moon |first7=Anne M. |date=2002-10-01 |title=An <i>Fgf8</i> mouse mutant phenocopies human 22q11 deletion syndrome." |journal=Development October 2002|publisher=The Company of Biologists |volume=129( |issue=19) p4591|pages=4591–4603 |doi=10.1242/dev.129.19.4591 |issn=1477-9129 4603|pmc=1876665 {{PMID|pmid=12223415}} {{PMC|1876665doi-access=free}}. Accessed 19 November 2012.</ref>
=== GATA ===
[[GATA transcription factor]]s, which are complex molecules that bind to the DNA sequence ''GATA'', play a critical role in cell lineage differentiation restriction during cardiac development. The primary function of [[GATA6]] in cardiovascular development is to regulate the morphogenetic patterning of the outflow tract and aortic arch. When [[GATA6]] is inactivated in CNCCs, various cardiovascular defects such as persistent truncus arteriosus and interrupted aortic arch may occur. This phenotype (anomaly) was also observed when GATA6 was inactivated within vascular smooth muscle cells.<ref name="Lepore (2006)">{{Cite journal |last=Lepore |first=J. J. et|date=2006-03-23 al [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1409743/pdf/JCI0627363.pdf "|title=GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis |url=http://www."]jci.org/articles/view/27363/files/pdf |journal=Journal of Clinical Investigation 3 April 2006,|volume=116 116(|issue=4) p929 - 939 {{PMID|16557299}}pages=929–939 {{PMC|1409743}} {{doi|=10.1172/JCI27363}}. Accessed|issn=0021-9738 19|pmc=1409743 November|pmid=16557299 2012.|doi-access=free}}</ref> GATA6 in combination with Wnt (Wnt2-GATA6) plays a role in the development of the posterior pole of the heart (the inflow tract).<ref name="Tian (2010)">{{Cite journal |last1=Tian Y|first1=Ying |last2=Yuan |first2=Lijun |last3=Goss |first3=Ashley M. et|last4=Wang al|first4=Tao [https://www|last5=Yang |first5=Jifu |last6=Lepore |first6=John J.ncbi |last7=Zhou |first7=Diane |last8=Schwartz |first8=Robert J.nlm |last9=Patel |first9=Vickas |last10=Cohen |first10=Ethan David |last11=Morrisey |first11=Edward E.nih.gov/pmc/articles/PMC2846539/pdf/nihms177061.pdf "|display-authors=6 |date=2010 |title=Characterization and inIn vivoVivo pharmacologicalPharmacological rescueRescue of a Wnt2-GATA6Gata6 pathwayPathway requiredRequired for cardiacCardiac inflowInflow tractTract developmentDevelopment |url=https://www."]cell.com/article/S153458071000047X/pdf |journal=Developmental Cell 16 February 2010 |volume=18(2) p275 - 287 pm |issue=28465392 {{PMID|20159597}}pages=275–287 {{doi|doi=10.1016/j.devcel.2010.01.008}} Accessed|pmc=2846539 19|pmid=20159597 November 2012.|doi-access=free}}</ref>
== CNCCS and ischaemic heart disease ==
There is interest amongst researchers as to whether CNCCs can be used to repair human heart tissue. [[Myocardial infarction|Heart attacks]] in humans are common and their rate of mortality is high. There are emergency treatments that hospitals can administer, such as [[angioplasty]] or [[surgery]], but after that patients will likely be on medication for the long term and are more susceptible to heart attacks in the future. Other complications of heart attacks include [[cardiac arrhythmia]]s and [[heart failure]].<ref name="Canada (2012)">[{{Cite web |title=Statistics |url=http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm "Canadian Heart and Stroke Foundation statistics."] {{Webarchive|archive-url=https://web.archive.org/web/2012120317584620130104212608/http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm# |archive-date=20122013-1201-03 }} Canadian04 |website=Heart and Stroke Foundation Accessedof 20 November 2012.Canada}}</ref>
Although CNCCs are important in embryos, some CNCCs are retained in a dormant state to adulthood where they are called ''[[neural crest]] [[stem cells]]''. In 2005, Tomita transplanted neural crest stem cells from mammal hearts to the neural crest of chick embryos. These CNCCs were shown to migrate into the developing heart of the chick using the same dorsolateral pathway as the CNCCs, and differentiate into neural and glial cells.<ref name="Tomita (2005)">{{Cite journal |last1=Tomita Y.|first1=Yuichi et|last2=Matsumura al|first2=Keisuke "|last3=Wakamatsu |first3=Yoshio |last4=Matsuzaki |first4=Yumi |last5=Shibuya |first5=Isao |last6=Kawaguchi |first6=Haruko |last7=Ieda |first7=Masaki |last8=Kanakubo |first8=Sachiko |last9=Shimazaki |first9=Takuya |last10=Ogawa |first10=Satoshi |last11=Osumi |first11=Noriko |last12=Okano |first12=Hideyuki |last13=Fukuda |first13=Keiichi |display-authors=6 |date=2005-09-26 |title=Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart |url=https://rupress."org/jcb/article-pdf/170/7/1135/1320291/jcb17071135.pdf J|journal=The CellJournal Biolof SeptemberCell 2005,Biology |volume=170(7) p1135 - 1146 {{PMC|2171522}}issue=7 {{PMID|16186259}}pages=1135–1146 {{|doi|=10.1083/jcb.200504061}} Accessed|issn=1540-8140 20|pmc=2171522 November|pmid=16186259 2012.|doi-access=free}}</ref>
Tamura's study of 2011 examined the fate of CNCCs after a heart attack (myocardial infarction) in young mice. The CNCCs in the young mice were tagged with enhanced [[green fluorescent protein]] (EGFP) and then traced. Tagged CNCCs were concentrated in the cardiac outflow tract, and some were found in the ventricular myocardium. These cells were also shown to be differentiating into cardiomyocytes as the heart grew. Although less were found, these EGFP-labelled CNCCs were still present in the adult heart. When a heart attack was induced, the CNCCs aggregated in the ischemic border zone area (an area of damaged tissue that can still be saved) and helped contribute to the regeneration of the tissue to some extent via differentiation into cardiomyocytes to replace the necrotic tissue.<ref name="Tamura (2011)">{{Cite journal |last1=Tamura y.|first1=Yuichi et|last2=Matsumura al|first2=Keisuke [http://atvb.ahajournals.org/content/31/3/582.full.pdf|last3=Sano "Neural|first3=Motoaki crest-derived|last4=Tabata stem|first4=Hidenori cells|last5=Kimura migrate|first5=Kensuke and|last6=Ieda differentiate|first6=Masaki into|last7=Arai cardiomyocytes|first7=Takahide after|last8=Ohno myocardial|first8=Yohei infarction."]|last9=Kanazawa Journal|first9=Hideaki of|last10=Yuasa the|first10=Shinsuke American|last11=Kaneda Heart|first11=Ruri Association|last12=Makino January|first12=Shinji |last13=Nakajima |first13=Kazunori |last14=Okano |first14=Hideyuki |last15=Fukuda |first15=Keiichi |display-authors=6 |date=2011 |title=Neural Crest–Derived Stem Cells Migrate and Differentiate Into Cardiomyocytes After Myocardial Infarction |journal=Arteriosclerosis, 31(3)Thrombosis, p582and -Vascular 589Biology Accessed|volume=31 20|issue=3 November|pages=582–589 2012|doi=10.1161/ATVBAHA.110.214726 |pmid=21212399 |issn=1079-5642 |doi-access=free}}</ref><ref name="Axford (1988)">{{Cite journal |last1=Axford-Gatley |first1=R. A. and |last2=Wilson |first2=G. J. "|title=The "border zone" in myocardial infarction:. anAn ultrastructural study in the dog using an electron-dense blood flow marker." Am.|journal=The J.American Pathol.Journal Juneof Pathology |date=1988, |volume=131( |issue=3) p452|pages=452–464 - 464 {{PMC|pmc=1880711}} {{PMID|pmid=3381878}}. Accessed 20 November 2012.</ref>
== References ==
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