Neural crest cells Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, Per ...

are multipotent cells required for the development of cells, tissues and organ systems. 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 The pharyngeal arches, also known as visceral arches'','' are structures seen in the embryonic development of vertebrates that are recognisable precursors for many structures. In fish, the arches are known as the branchial arches, or gill arch ...

3, 4 and 6. 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. Ablation of the complex often leads to impaired myocardial functioning similar to symptoms present in

DiGeorge syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent in ...

. Consequently, the removal of cardiac crest cells that populate in pharyngeal arches has flow on effects on the

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

parathyroid Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...

and

thyroid gland The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobe (anatomy), lobes. The lower two thirds of the lobes are connected by a thin band of Connective tissue, tissue cal ...

Neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...

cells are a group of temporary,

multipotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

(can give rise to some other types of cells but not all) cells that are pinched off during the formation of the

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, a ...

(precursor to the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...

and brain) and therefore are found at the dorsal (top) region of the neural tube during development.Kirby M
"Cardiac morphogenesis: recent research advances."
''Pediatric Research.'' 1987 21(3) 219 - 224. They are derived from the

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...

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.Gilbert S. F
"Developmental biology."
Sinauer Associates, Massachusetts, 2010 p373 - 389. They migrate throughout the body and create a large number of differentiated cells such as

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s, glial cells, pigment-containing cells in skin, skeletal tissue cells in the head, and many more. 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 The pharyngeal arches, also known as visceral arches'','' are structures seen in the embryonic development of vertebrates that are recognisable precursors for many structures. In fish, the arches are known as the branchial arches, or gill arch ...

es) and then into the 3rd, 4th and 6th pharyngeal arches and the cardiac outflow tract (OFT).Kuratani S. C. and Kirby M. L. "Migration and distribution of circumpharyngeal crest cells in the chick embryo: formation of the circumpharyngeal ridge and E/C8+ crest cells in the vertebrate head region." Anat. Rec. October 1992 234(2) p263 - 268 They extend from the

otic placode In embryology, the otic placode is a thickening of the ectoderm on the outer surface of a developing embryo from which the ear develops. The ear, including both the vestibular system and the auditory system, develops from the otic placode beginnin ...

s (the structure in developing embryos that will later form the ears) to the third

somite The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide in ...

s (clusters of

mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...

that will become skeletal muscle, vertebrae and dermis). The cardiac neural crest cells have a number of functions including creation of the muscle and

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

walls of large arteries; parts of the cardiac

septum In biology, a septum (Latin for ''something that encloses''; plural septa) is a wall, dividing a cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate. Examples Human anatomy * Interatri ...

; parts of the

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

and

glands. They differentiate into

melanocytes Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart. ...

and neurons and the

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...

and

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.

Pathway of the migratory cardiac neural crest cell

Induction

Neural induction The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...

is the differentiation of progenitor cells into their final designation or type. The progenitor cells which will become CNCCs are found in the

epiblast In amniote embryonic development, the epiblast (also known as the primitive ectoderm) is one of two distinct cell layers arising from the inner cell mass in the mammalian blastocyst, or from the blastula in reptiles and birds, the other layer is t ...

about Henson's node.Kirby M. K. and Hutson M. R
"Factors controlling cardiac neural crest cell migration."
Cell Adhesion and Migration, December 2010, 4(4) p609 - 621 . Progenitor cells are brought into the

neural fold The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with primary neurulation, meaning that it forms by the coming together of t ...

s. Molecules such as Wnt,

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...

(FGF) and

bone morphogenetic protein Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of piv ...

(BMP) provide

signal In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...

s which induce the progenitor cells to become CNCCs. 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.

Initial migration

After induction, CNCCs lose their cell to cell contacts. This allows them to move through the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

and interact with its components. The CNCCs, with the assistance of their

filopodia Filopodia (singular filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lame ...

and

lamellipodia The lamellipodium (plural lamellipodia) (from Latin ''lamella'', related to ', "thin sheet", and the Greek radical ''pod-'', "foot") is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional ...

(

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

containing extensions of

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

that allow a cell to probe its path of migration), leave the neural tube and migrate along a

dorsolateral Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

pathway to the circumpharyngeal ridge. 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 In geometry, a polygon () is a plane figure that is described by a finite number of straight line segments connected to form a closed ''polygonal chain'' (or ''polygonal circuit''). The bounded plane region, the bounding circuit, or the two tog ...

shape and proliferate at a faster rate than trailing cells.

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. 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. From here, a subpopulation of cells will develop into the endothelium of the

aortic arch The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea. Structure The aorta begins a ...

arteries while others will migrate into the outflow tract to form the aorticopulmonary and truncal septa. Other ectomesenchymal cells will form the thymus and parathyroid glands.

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 The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

and increased motility and interaction with extracellular components in the matrix. An important step in this process is the suppression of adhesion protein

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...

present on

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

to initiate the migration process. This suppression mechanism occurs via the

growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

BMP signalling to turn on a transcriptional repressor Smad-interacting protein 1 (Sip1) and marks the beginning of the epithelial-mesenchymal transition.

Early migration

During migration, crest cells destined for pharyngeal arches maintain contact with each other via

and

. Short range local contact is maintained with lamellipodia whilst long range non-local contact is maintained with filopodia. During this process,

connexin 43 Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the ''GJA1'' gene on chromosome 6. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular co ...

(Cx43) regulates cell interaction by regulating the formation of channels known as

gap junctions Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

. Impaired Cx43 function in transgenic mice leads to altered coronary artery patterns and abnormal outflow tracts. Further gap junction signalling is dependent on a

cadherin Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...

mediated cell adhesion formed during cross talking with p120 catenin signalling. Appropriate outflow tract formation relies on a

morphogen A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various ...

concentration gradient set up by

(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. Cells located in rhombomeres 3and 5 undergo programmed cell death under signalling cues from

semaphorins Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorins ...

. The lack of cells in this region results in the formation of crest-free zones. The process of migration requires a permissive extracellular matrix. The

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

arginyltransferase creates this environment by adding an arginyl group onto newly synthesised proteins during

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...

. This process aids cells motility and ensures proteins the proteins contained within the actin cytoskeleton is prepped for migration.

Circumpharyngeal ridge

Cell migration towards the circumpharyngeal ridge is forced to paused to allow for the formation of the caudal pharyngeal arches. Little is known about this pausing mechanism, but studies conducted in chicks have uncovered the role of

expressed factors EphrinB3 and EphrinB4 in forming fibronectin attachments.

Caudal pharynx and arch artery condensation

Pharyngeal arches are tissues composed of mesoderm-derived cells enclosed by an external

and an internal

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...

. 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. 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. 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.

Aortic arch remodeling

The aortic arch arteries transport blood from the

aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ...

to the head and trunk of the

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

. 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. 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. The group of cells found in the third aortic arch gives rise to common

carotid arteries In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
subclavian artery In human anatomy, the subclavian arteries are paired major arteries of the upper thorax, below the clavicle. They receive blood from the aortic arch. The left subclavian artery supplies blood to the left arm and the right subclavian artery supplie ...

, whilst cells in the sixth aortic arch develops into the

pulmonary arteries A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and t ...

. 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.

Ablation of cardiac neural crest complex

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 Persistent truncus arteriosus (PTA), often referred to simply as truncus arteriosus, is a rare form of congenital heart disease that presents at birth. In this condition, the embryological structure known as the truncus arteriosus (embryology), t ...

. This arises when the arterial trunk fails to divide and cause the separation of

pulmonary artery A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and t ...

and aorta. This results in a lack of aorticopulmonary septum as the vessels which would normally disappear during normal development remains and interrupts the carotid vessels. The malformation of the heart and its associated great vessels depends on the extent and location of the cardiac neural crest complex ablation. 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. Mesencephalic neural crest cells interfere with normal development of cardiac outflow septation as its presence leads to persistent truncus arteriosus. However, the addition of trunk neural crest cells results in normal heart development. Other outcomes of cardiac outflow anomalies includes

Tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the ri ...

, Eisenmenger's complex, transposition of the great vessels and double outlet right ventricle.

Aortic arch arteries anomalies

Overriding aorta An overriding aorta is a congenital heart defect where the aorta is positioned directly over a ventricular septal defect (VSD), instead of over the left ventricle. The result is that the aorta receives some blood from the right ventricle, causing ...

is caused by the abnormal looping during early development of the heart and is accompanied with ventricular septal defects. 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

as opposed to the left ventricle. This results in a reduction of oxygenated blood as the aorta receives some deoxygenated blood from the flow of the

right ventricle A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...

. There is a reduction in the quantity of endothelial tubes of

ectomesenchyme Ectomesenchyme has properties similar to mesenchyme. The origin of the ectomesenchyme is disputed. It is either like the mesenchyme, arising from mesodermic cells, or conversely arising from neural crest cells. The neural crest is a critical group ...

in pharyngeal arches that surround the aortic arch arteries. Other outcomes of aortic arch artery anomalies includes a double aortic arch, variable absence of the carotid arteries and left aortic arch.

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 Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

. Despite an increase in embryonic

stroke volume In cardiovascular physiology, stroke volume (SV) is the volume of blood pumped from the left ventricle per beat. Stroke volume is calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood i ...

and

cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: t ...

, this compensation of decreased contraction results in misalignment of the development vessels due to incomplete looping of the cardiac tube. In an adult heart, myocardium contraction occurs via

excitation-contraction coupling Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as w ...

whereby cellular

depolarisation In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

occurs and allows an influx of calcium via

voltage-gated calcium channels Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabili ...

. A subsequent reuptake of calcium into the

sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other Cell (biology), cells. The main function of the SR is to store calcium ions (Ca2+). Calcium in bio ...

causes a decrease in intracellular calcium to cause myocardium relaxation. 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.

Pulmonary venous system

During

cardiogenesis Heart development, also known as cardiogenesis, refers to the prenatal development of the heart. This begins with the formation of two endocardial tubes which merge to form the tubular heart, also called the primitive heart tube. The heart is the ...

, 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.

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.

Location

Into the

and

Truncus arteriosus (embryology) The truncus arteriosus is a structure that is present during embryonic development. It is an arterial trunk that originates from both ventricles of the heart that later divides into the aorta and the pulmonary trunk. Structure The truncus arterio ...

, forming the

aorticopulmonary septum The aorticopulmonary septum is developmentally formed from neural crest, specifically the cardiac neural crest, and actively separates the aorta and pulmonary arteries and fuses with the interventricular septum within the heart during heart develop ...

and the

smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...

great arteries The great arteries are the primary arteries that carry blood away from the heart, which include: * ''Pulmonary artery'': the vessel that carries oxygen-depleted blood from the right ventricle to the lungs. * ''Aorta'': the blood vessel through whic ...

. Anterior of the aorta to become the four pre-aortic ganglia: (

celiac ganglion The celiac ganglia or coeliac ganglia are two large irregularly shaped masses of nerve tissue in the upper abdomen. Part of the sympathetic subdivision of the autonomic nervous system (ANS), the two celiac ganglia are the largest ganglia in ...

superior mesenteric ganglion The superior mesenteric ganglion is a ganglion in the upper part of the superior mesenteric plexus. It lies close to the origin of the superior mesenteric artery. Structure The superior mesenteric ganglion is the synapsing point for one of the p ...

inferior mesenteric ganglion Inferior may refer to: * Inferiority complex * An anatomical term of location * Inferior angle of the scapula, in the human skeleton * ''Inferior'' (book), by Angela Saini * ''The Inferior'', a 2007 novel by Peadar Ó Guilín See also *Junior (d ...

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.

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. 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. A variety of

s and

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s in the extracellular matrix signal cells and direct them toward a specific arch. For example, signalling by

FGF8 Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the ''FGF8'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and ...

directs CNCCS to the fourth arch and keeps the cells viable.

Migration to the cardiac outflow tract

The cardiac outflow tract is a temporary structure in the developing embryo that connects the ventricles with the

aortic sac The aortic sac or aortic bulb is a dilated structure in mammalian embryos, lined by endothelial cells and is the most distal part of the truncus arteriosus. It is the primordial vascular channel from which the aortic arches arise (and eventually th ...

. Some CNCCs migrate beyond the pharyngeal arches to the cardiac outflow tract. CNCCS in the cardiac outflow tract contribute to the formation of the cardiac

ganglia A ganglion is a group of neuron cell bodies in the peripheral nervous system. In the somatic nervous system this includes dorsal root ganglia and trigeminal ganglia among a few others. In the autonomic nervous system there are both sympatheti ...

and

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...

at the junction of the subaortic and sub pulmonary

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...

(muscular heart tissue) of the outflow tract. A smaller portion of the CNCCs migrate to the proximal outflow tract where they help to close the ventricular outflow septum.

Molecular pathways

Many signaling molecules are required for the differentiation, proliferation, migration and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

of the CNCCs. The molecular pathways involved include the Wnt, Notch, BMP,

and

GATA Davionte Ganter, known professionally as GaTa, is an American rapper and actor known for his role in the FXX TV series ''Dave'', as well as for being the hype man for rapper Lil Dicky throughout his career as well as on the show. Early life a ...

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. 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 The endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels. The endocardium also provides protection to the va ...

, myocardium, and

epicardium The pericardium, also called pericardial sac, is a double-walled sac containing the heart and the roots of the great vessels. It has two layers, an outer layer made of strong connective tissue (fibrous pericardium), and an inner layer made of ...

. The CNCCs themselves are the precursors to vascular smooth muscle cells and cardiac neurons.Brown C. and Baldwin H. "Neural crest contribution to the cardiovascular system." Advances in Experimental Medicine 2006, 589 p134 - 154 . Accessed 19 November 2012. For example, CNCCs are required for the formation of the

(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

. If this signalling is disrupted or there are defects in the CNCCS, cardiovascular anomalies may develop. These anomalies include

(PTA),

double outlet right ventricle Double outlet right ventricle (DORV) is a form of congenital heart disease where both of the great arteries connect (in whole or in part) to the right ventricle (RV). In some cases it is found that this occurs on the left side of the heart rather t ...

(DORV),

tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the ri ...

and

.Pompa J. L. and Epstein J. A. "Coordination tissue interactions: notch signalling in cardiac development and disease." Developmental Cell, February 2012, 22(2) p244 - 264. Accessed 19 November 2012.

Wnt

Wnt proteins are extracellular

s that activate intracellular signalling pathways. There are two types of pathways: canonical and non-canonical. The classic canonical Wnt pathway involves

β-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcriptio ...

protein as a signaling mediator. Wnt maintains β-catenin by preventing against

Proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

degradation. Thus, β-catenin is stabilized in the presence of Wnt and regulates gene transcription through interaction with TCF/LEF transcription factors.Gessert S. and Kuhl M
"The multiple phases and faces of wnt signaling during cardiac differentiation and development."
Circulation Research, 2010 107(2) p 186 - 199 . Accessed 19 November 2012. The canonical Wnt/β-catenin pathway is important for control of cell proliferation.Kirby M. L. and Hutson M. R
"Factors controlling cardiac neural crest cell migration."
Cell adhesion and migration, December 2010 4(4). Accessed 20 November 2012. The non-canonical Wnt pathway is independent of β-catenin and has an inhibitory effect on canonical Wnt signaling. Wnt signaling pathways play a role in CNCC development as well as OFT development. In mice, decrease of β-catenin results in a decrease in the proliferation of CNCCs. Downregulation of the Wnt coreceptor

Lrp6 Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the ''LRP6'' gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Structure LRP6 is a tr ...

leads to a reduction of CNCCs in the dorsal neural tube and in the pharyngeal arches, and results in ventricular, septal, and OFT defects. Canonical Wnt signaling is especially important for cell cycle regulation of CNCC development and the initiation of CNCC migration. Non-canonical Wnt signaling plays a greater role in promoting cardiac differentiation and OFT development.

Notch

Notch is a transmembrane protein whose signaling is required for differentiation of CNCCs to vascular

cells and for proliferation of cardiac

myocytes A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

(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.Niessen K. and Karsan A. "Notch signaling in cardiac development." Circulation Research 2008, 102 p1169 - 1181 . Accessed 20 November 2012. In humans, mutations in Notch most often result in bicuspid aortic valve disease and calcification of the aortic valve.Garg V. et a
"Mutations in NOTCH1 cause aortic valve disease."
Nature September 2005 437(7056) p 270 - 274. Accessed 20 November 2012.

Bone morphogenetic proteins

Bone morphogenetic protein Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of piv ...

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.Kaartinen V. et al "Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells". Development July 2004, 131(14) p3481 - 3490 Accessed 19 November 2012.

Fibroblast growth factor 8

Fibroblast growth factor 8 Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the ''FGF8'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and ...

(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.Abu-Issa R. et a
"FGF8 is required for pharyngeal arch and cardiovascular development in the mouse."
Development October 2012 129(19) p4163 - 4625 Accessed 19 November 2012.Frank D. U. et al "FGF8 mouse mutant phenocopies human 22q11 deletion syndrome." Development October 2002, 129(19) p4591 - 4603 . Accessed 19 November 2012.

GATA

GATA transcription factor GATA transcription factors are a family of transcription factors characterized by their ability to bind to the DNA sequence "GATA". GATA transcription factors have been correlated to their broader influence on stem cell development. Findings ho ...

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 Transcription factor GATA-6, also known as GATA-binding factor 6 (GATA6), is protein that in humans is encoded by the ''GATA6'' gene. The gene product preferentially binds (A/T/C)GAT(A/T)(A) of the consensus binding sequence. Clinical significa ...

in cardiovascular development is to regulate the morphogenetic patterning of the outflow tract and aortic arch. When

is inactivated in CNCCs, various cardiovascular defects such as persistent truncus arteriorus and interrupted aortic arch may occur. This phenotype (anomaly) was also observed when GATA6 was inactivated within vascular smooth muscle cells.Lepore J. J. et a
"GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis."
Journal of Clinical Investigation 3 April 2006, 116(4) p929 - 939 . Accessed 19 November 2012. GATA6 in combination with Wnt (Wnt2-GATA6) plays a role in the development of the posterior pole of the heart (the inflow tract).Tian Y. et a
"Characterization and in vivo pharmacological rescue of a Wnt2-GATA6 pathway required for cardiac inflow tract development."
Developmental Cell 16 February 2010 18(2) p275 - 287 pm =2846539 Accessed 19 November 2012.

CNCCS and ischaemic heart disease

There is interest amongst researchers as to whether CNCCs can be used to repair human heart tissue.

Heart attacks A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tra ...

in humans are common and their rate of mortality is high. There are emergency treatments that hospitals can administer, such as

angioplasty Angioplasty, is also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atheroscle ...

surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

, 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 Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

s and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

."Canadian Heart and Stroke Foundation statistics."
Canadian Heart and Stroke Foundation Accessed 20 November 2012. Although CNCCs are important in embryos, some CNCCs are retained in a dormant state to adulthood where they are called ''

neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...

stem cells In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

''. 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.Tomita Y. et al "Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart." J Cell Biol September 2005, 170(7) p1135 - 1146 Accessed 20 November 2012. 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 The green fluorescent protein (GFP) is a protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. The label ''GFP'' traditionally refers to the protein first isolated from the jellyfish ''Aequorea ...

(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.Tamura y. et a
"Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction."
Journal of the American Heart Association January 2011, 31(3) p582 - 589 Accessed 20 November 2012.Axford-Gatley R. A. and Wilson G. J. "The "border zone" in myocardial infarction: an ultrastructural study in the dog using an electron-dense blood flow marker." Am. J. Pathol. June 1988, 131(3) p452 - 464 . Accessed 20 November 2012.

References

{{Authority control Embryology of cardiovascular system Embryology of nervous system