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{{Infobox embryology
| Name = Cardiac neural crest complex
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}}
[[Neural crest cells]] are multipotent cells required for the development of cells, tissues and organ systems.<ref name=
A subpopulation of neural crest cells are the '''cardiac neural crest
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=
[[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
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
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 ==
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=== 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
=== 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=
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=
===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=
===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”">{{
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=
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=
===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=
===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
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
The aortic arch arteries transport blood from the [[aorta]] to the head and trunk of the [[embryo]].<ref name=
==Ablation of cardiac neural crest complex==
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===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=
Other outcomes of cardiac outflow anomalies includes [[Tetralogy of Fallot]],
===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=
===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">{{
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
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)">
=== 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 [[
Wnt signaling pathways play a role in CNCC development as well as OFT development.<ref name="Gessert (2010)" /> In mice, decrease of
=== 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)">
=== 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
=== 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
=== 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
== 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)">
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
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
== References ==
{{reflist
{{Development of nervous system}}▼
{{Authority control}}▼
[[Category:Embryology of cardiovascular system]]
[[Category:Embryology of nervous system]]
▲{{Development of nervous system}}
▲{{Authority control}}
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