*#REDIRECT [[ CranialCardiac neural crest]] ▼{{Merge to|Cardiac neural crest|discuss=Talk:Cardiac neural crest cells#Proposed merge with Cardiac neural crest complex|date=December 2019}}
{{Infobox embryology
| Name = Cardiac neural crest complex
| Latin = complexus cristae neuralis cardiacus
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{{R from merge}}
[[Neural crest cells]] are multipotent cells required for the development of cells, tissues and organ systems.<ref name= "pmid17619792" >{{cite journal |vauthors= Snider P, Olaopa M, Firulli AB, Conway SJ | 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}}</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" >{{cite journal |vauthors= Kirby ML, Hutson MR | 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}}</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" >{{cite journal |vauthors= Hutson MR, Kirby ML | 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 }}</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" >{{cite journal |vauthors= Le Lièvre CS, Le Douarin NM| 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>
==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" >{{cite journal |vauthors= Le Lièvre CS, Le Douarin NM| title = Role of neural crest in congenital heart disease | journal = Circulation | volume = 82 | issue = 2 | pages = 332–340| date = 1990 | pmid = 2197017| doi = 10.1161/01.CIR.82.2.332 | 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" >{{cite journal |vauthors= Bajolle F, Zaffran S, Meilhac SM, Dandonneau M, Chang T, Kelly RG| 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 | issue = 1 | pages = 25–34| date = 2008 | pmid = 18005956| doi = 10.1016/j.ydbio.2007.09.023 }}</ref> Other ectomesenchymal cells will form the thymus and parathyroid glands.<ref name= "pmid6606851" >{{cite journal |vauthors= Bockman DE, Kirby ML| title = Dependence of thymus development on derivatives of the neural crest | journal = Science| volume = 223| issue =4635 | pages = 498–500| date = 1984| pmid = 6606851| doi = 10.1126/science.6606851 | bibcode = 1984Sci...223..498B }}</ref>
===Epithelial-mesenchymal transition===
Prior to migration, during a process known as epithelial-mesenchymal transition, 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" >{{cite journal |vauthors= Hay ED| 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}}</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" >{{cite journal |vauthors= Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F| title = The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion | journal = Molecular Cell| volume = 7 | issue = 6| pages = 1267–1278| date = 2007| pmid = 11430829 | doi = 10.1016/S1097-2765(01)00260-X }}</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”">{{cite journal |vauthors= Teddy JM, Kulesa PM| title = In vivo evidence for short-and long-range cell communication in cranial neural crest cells | journal = Development| volume = 131| issue=24 | pages =6141–6151| date = 2004| pmid = 15548586| doi = 10.1242/dev.01534 | doi-access = free}}</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" >{{cite journal |vauthors= Huang GY, Wessels A, Smith BR, Linask KK, Ewart JL, Lo CW| title = Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development | journal = Developmental Biology| volume = 198| issue = 1 | pages = 32–44| date = 1998| pmid = 9640330| doi = 10.1006/dbio.1998.8891 }}</ref> Further gap junction signalling is dependent on a [[cadherin]] mediated cell adhesion formed during cross talking with p120 catenin signalling.<ref name= "pmid11449002" >{{cite journal |vauthors= Xu X, Li WE, Huang GY, Meyer R, Chen T, Luo Y, Thomas MP, Radice GL, Lo CW | 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 }}</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" >{{cite journal |vauthors= Abu-Issa R, Smyth G, Smoak I, Yamamura K, Meyers EN | title = Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse | journal = Development| volume = 129| issue = 19 | pages = 4613–4625| date = 2002| 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" >{{cite 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| 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 }}</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" >{{cite journal| vauthors= Kurosaka S, Leu NA, Zhang F, Bunte R, Saha S, Wang J, Guo C, He W, Kashina A| title = Arginylation-dependent neural crest cell migration is essential for mouse development. | journal = PLoS Genetics| volume = 6| issue =3 | pages = e1000878| date = 2010| pmid =20300656| pmc = 2837401 | doi = 10.1371/journal.pgen.1000878 }}</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" >{{cite journal |vauthors= Santiago A, Erickson CA | title = Ephrin-B ligands play a dual role in the control of neural crest cell migration | journal = Development| volume = 129| issue = 15 | pages = 3621–3623| date = 2002| 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 the protein filopedia that acts 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 remodelling===
The aortic arch arteries transport blood from the [[aorta]] to the head and trunk of the [[embryo]].<ref name= "pmid9558464" >{{cite journal |vauthors= Creazzo TL, Godt RE, Leatherbury L, Conway SJ, Kirby ML | title = Role of cardiac neural crest cells in cardiovascular development | journal = Annual Review of Physiology| volume = 60| issue = 1 | pages = 267–286| date = 1998| pmid = 9558464| doi = 10.1146/annurev.physiol.60.1.267 }}</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==
[[File:Common abnormalities that arises during cardiac neural crest differentiation.png|thumb|A comparison between normal development and common abnormalities that arises during cardiac neural crest differentiation]]
===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" >{{cite journal |vauthors= van den Hoff MJ, Moorma AF | title = Cardiac neural crest: the holy grail of cardiac abnormalities?| journal = Cardiovascular Research| volume = 47| issue = 2 | pages = 212–216| date = 2000| pmid = 10946058| doi = 10.1016/s0008-6363(00)00127-9| 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" >{{cite journal |vauthors= Kirby ML | title = Plasticity and predetermination of mesencephalic and trunk neural crest transplanted into the region of the cardiac neural crest | journal = Developmental Biology| volume = 134| issue=2 | pages = 402–412| date = 1989| pmid = 2744240| doi = 10.1016/0012-1606(89)90112-7 }}</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" >{{cite journal |vauthors= Phillips III MT, Waldo K, Kirby ML| title = Neural crest ablation does not alter pulmonary vein development in the chick embryo. | journal = The Anatomical Record| volume = 223| issue =3 | pages = 292–298| date = 1989| pmid = 2923280| doi = 10.1002/ar.1092230308}}</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">{{cite journal |vauthors=Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM |title=Fate of the mammalian cardiac neural crest |journal=Development |volume=127 |issue=8 |pages=1607–16 |date=April 2000 |pmid=10725237 |doi= |url=http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=10725237}}</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]]).
==See also==
*[[Neural crest]]
▲*[[Cranial neural crest]]
*[[Trunk neural crest]]
==References==
{{Reflist}}
==External links==
* {{EmbryologyUNSW|Notes/ncrest}}
{{Development of nervous system}}
{{Authority control}}
[[Category:Embryology of nervous system]]
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