2018 Group Project 4: Difference between revisions

From Embryology
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=== 1. Induction ===
=== 1. Induction ===


Initially, NCCs are morphologically similar to other neuroepithelial cells and cannot be differentiated from them. With contact-mediated inductive signals from the surface ectoderm and underlying mesoderm through a process known as Induction where progenitor cells begin to differentiate {{#pmid:PMC3552505|PMC3552505}}. Progenitor cells are found in the epiblast around Henson's node and are brought into the neural folds where signalling molecules induces the progenitor cells to turn into CNCCs.
Initially, NCCs are morphologically similar to other neuroepithelial cells and cannot be differentiated from them. With contact-mediated inductive signals from the surface ectoderm and underlying mesoderm through a process known as Induction where progenitor cells begin to differentiate {{#pmid:PMC3552505|PMC3552505}}. Progenitor cells are found in the epiblast around Henson's node and are brought into the neural folds where signalling molecules will induce the progenitor cells to turn into CNCCs {{#pmid:PMC3552505|PMC3552505}}. While key signalling regulators of neural crest cell formation such as bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) have been identified in species such as fish and avians, there is currently no evidence that suggests the same factors play a role in mammalian neural crest cell induction, thus more studies have to be carried out to identify the signalling pathway for mammalian neural crest cell formation {{#pmid:PMC3552505|PMC3552505}}. Studies have also shown that if BMP levels are too high or low,  the progenitor cells will not be able to migrate, thus an intermediate level of BMP is ideal for the induction process.{{#pmid:PMC3011257|PMC3011257}} As for the other signalling cascades involved, little information is known.
 
 
 
Studies have shown that if BMP levels are too high or low,  the progenitor cells will not be able to migrate, thus an intermediate level of BMP is ideal for the induction process.{{#pmid:PMC3011257|PMC3011257}} As for the other signalling cascades involved, little information is known.
 
 
Although the bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling families have each been identified as key signaling regulators of neural crest cell formation in diverse species such as avians, fish, and amphibians, there is no conclusive evidence that supports an absolute role for these same factors in mammalian neural crest cell induction (Crane and Trainor 2006). These signaling pathways appear to be more important for specifying cell-type differentiation within the mammalian neural crest cell lineage. Therefore, the signals and switches governing mammalian neural crest cell formation remain to be identified.
 
 
PMC3552505


=== 2. From Neural Crest to Circumpharyngeal Ridge ===
=== 2. From Neural Crest to Circumpharyngeal Ridge ===

Revision as of 15:04, 1 October 2018

Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion

Project Pages are currently being updated (notice removed when completed)

Neural Crest and Cardiac Development

Brief Overview of The Cardiovascular System

Introduction of the Heart

The heart is a muscular organ which plays a critical role in the circulatory system by mechanically pumping blood to various organs around the body for the exchange of nutrients and gases. It is located at the center of the chest, right behind the sternum and is tilted slightly to the left.

Anatomy and Physiology of the Heart

Structure of the Adult Human Heart

The heart has four different chambers which are compartmentalized by semilunar and atrioventricular valves into the left and right atria and ventricles. The right atrium collects blood returning from the body (deoxygenated), while the left atrium collects blood (oxygenated) returning from the lungs. The right ventricle pumps blood to the lungs and the left ventricle propels blood into the aorta where blood is dispersed to the rest of the body for consumption. There are four valves located in the heart that prevent the backflow of blood. The average heart rate for an adult is anywhere between 60-100 beats per minute, whereas for babies, it can be higher around 120-140 beats per minute. The heart rates of well-conditioned athletes can even be below 40 beats per minute.

http://baldaivirtuves.info/copyright (What is this for?)

Path taken by deoxygenated blood through the heart

Inferior and superior vena cava--->Right Atrium--->through Tricuspid valve--->Right Ventricle--->Pulmonary Semi-Lunar Valve--->Pulmonary Trunk--->left & Right Pulmonary arteries---> Left & Right Pulmonary Veins---> Left Atrium---> Bicuspid Valve---> Left Ventricle---> Aortic Semilunar Valve---> Trunk of the Aorta---> Aortic Arteries---> Descending Aorta.

After the blood has travelled through the body and the oxygen has been consumed by the bodies tissues, the blood returns to the heart via veins and the inferior vena cava and superior vena cava. The process repeats.

Histology of the Heart
Cardiovascular System

Development of the Cardiovascular System

Development of the cardiovascular system begins with the formation of two endocardial tubes that merge together to form the tubular heart. These loop together and separate into the four chambers and paired arterial trunks form the adult heart. The tubular heart differentiates into the truncus arterioles, bulbus cordis, primitive ventricle, primitive atrium and the sinus venosus. The truncus arteriosus splits into the ascending aorta and pulmonary artery. The bulbus cordis forms part of the ventricles. The sinus venosus connects to the fetal circulation. Septa form within the atria and ventricles to separate the left and right sides of the heart.


<html5media width="480" height="358">https://www.youtube.com/embed/5DIUk9IXUaI</html5media>

Week 2 - 3 *Bilateral cardiogenic areas form
Week 3 - 4
  • Mesoderm splitting
  • Folding brings heart tubes into the ventral midline
  • Heart tube fusion
  • Heart tube begins to beat
Week 4 - 5
  • Heart looping
  • Neural crest migration starts
  • Dorsal and ventral endocardial cushions fused
  • Foramen premium closed, septum secundum begins to develop
Week 5-6
  • Deep, muscular inter ventricular septum
  • Bulbar ridges and trabeculations evident
Week 7
  • Aortic and pulmonary trunks cleave
  • Valves developed

Cardiac Neural Crest Cells

Neural crest cells are a population of multipotent cells which arises during embryonic development at the dorsal neural tube. Neural crest cells originate from the dorsal-most region of the neural tube. These cells are capable of migrating and differentiating throughout the body to give rise to many different cell types. Cardiac neural crest cells (CNCCs) are a subpopulation of the cranial neural crest cells and migrate ventrally from the dorsal neural tube PubmedParser error: Invalid PMID, please check. (PMID: [1]). CNCCs will then proceed and fall in place into third, fourth and the sixth caudal pharyngeal arches as they develop during their migration to the cardiac outflow tract. They will form condensed mesenchymal cells of the aorticopulmonary septation complex and also differentiate into cardiac ganglia. (https://www.sciencedirect.com/science/article/pii/B9780123943118000133?via%3Dihub) NCCs are necessary for aortic arch artery remodeling and outflow tract septation (OFT).Odelin G, Faure E, Coulpier F, Di Bonito M, Bajolle F, Studer M, Avierinos JF, Charnay P, Topilko P & Zaffran S. (2018). Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. Development , 145, . PMID: 29158447 DOI.

Cardiac neural Cells can develop into:

  • Melanocytes near the heart region
  • neurons associated with cardiac innervation
  • cartilage
  • connective tissue (they form the connective tissue wall of the large arteries from the heart, as well as the septum between the branches in the heart)
  • provide signals required for the maintenance and differentiation of the other cell layers in the pharyngeal apparatus

Odelin G, Faure E, Coulpier F, Di Bonito M, Bajolle F, Studer M, Avierinos JF, Charnay P, Topilko P & Zaffran S. (2018). Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. Development , 145, . PMID: 29158447 DOI.

Early Development

1. Induction

Initially, NCCs are morphologically similar to other neuroepithelial cells and cannot be differentiated from them. With contact-mediated inductive signals from the surface ectoderm and underlying mesoderm through a process known as Induction where progenitor cells begin to differentiate PubmedParser error: Invalid PMID, please check. (PMID: [2]). Progenitor cells are found in the epiblast around Henson's node and are brought into the neural folds where signalling molecules will induce the progenitor cells to turn into CNCCs PubmedParser error: Invalid PMID, please check. (PMID: [3]). While key signalling regulators of neural crest cell formation such as bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) have been identified in species such as fish and avians, there is currently no evidence that suggests the same factors play a role in mammalian neural crest cell induction, thus more studies have to be carried out to identify the signalling pathway for mammalian neural crest cell formation PubmedParser error: Invalid PMID, please check. (PMID: [4]). Studies have also shown that if BMP levels are too high or low, the progenitor cells will not be able to migrate, thus an intermediate level of BMP is ideal for the induction process.PubmedParser error: Invalid PMID, please check. (PMID: [5]) As for the other signalling cascades involved, little information is known.

2. From Neural Crest to Circumpharyngeal Ridge

The cardiac neural crest is located caudally. The cells undergo an epithelial-to-mesenchymal transition, to emigrate from the neural tube, to the circumpharyngeal ridge PubmedParser error: Invalid PMID, please check. (PMID: [6]).There are multiple signalling factors which controls the migration of cardiac neural crest cells.

  • Snail2 inhibits expression of cadherins PubmedParser error: Invalid PMID, please check. (PMID: [7]).
  • RhoA/B, a GTPase protein, regulates and remodels the actin cytoskeleton of the cells to alter the planar cell polarity to allow neural crest migration PubmedParser error: Invalid PMID, please check. (PMID: [8]).
  • CNCC expresses integrin receotors and MMP-2 to allow them to migrate on fibronectin in extracellular matrix which is believed to provide a permissive environment to allow the migration of crest cells to the circumpharyngeal ridge {{#pmid:PMC3011257|PMC3011257}.

3. Formation of Pharyngeal Arches and Cardiac Outflow Tract

CNCCs express different factors that target the cells to the pharyngeal arches. Slit cells can target cells to migrate to arch 3. FGF-8 targets for arch 4. EphA targets for arch 6. Rac1 and Sdf1 are both expressed in the cells, causing them to condensate around the arch arteries. Semaphorin is expressed and causes the cells to migrate further to the cardiac outflow tract. Notch and BMP are then expressed condensing the cells, forming the semilunar valve and aoticopulmonary septum.

  • The 3rd arch is dedicated in the formation of the cartoid system. It forms the left and right common carotid arteries which will sprout into internal and external carotid arteries by angiogenesis PubmedParser error: Invalid PMID, please check. (PMID: [9]).
  • The 4th arch gives rise to the definitive aortic arch along with the pulmonary artery.
  • The 6th arch initially develops into the pulmonary trunk that emerges from the right ventricles, but this structure will be remodeled asymmetrically and gives rise to the ductus arteriosus which is a crucial embryonic structure that connects the pulmonary artery with the descending aorta for blood circulation in the fetus. This shunt allows blood from the right ventricle to bypass the lungs because the fetal blood is oxygenated through the placenta. At birth, as the lungs start their function, the ductus arteriosus closes allowing circulation through to the lungs to oxygenate the blood that subsequently reaches the systemic circulation of the newborn PubmedParser error: Invalid PMID, please check. (PMID: [10]).

Later Development

Development of the heart in the fetus and partitioning of the heart into four chambers

Outflow Septation

The distal outflow tract (trunks) septets into the aorta and pulmonary trunk via the fusion of two streams or prongs of cardiac neural crest that migrate into the distal outflow tract.

--> https://pdfs.semanticscholar.org/42cc/ee7fbb545ea6752e1c126cc2769e8e33e7b7.pdf

three components are responsible for forming the septa in the outflow tract:

  1. conus septum
  2. truncus septum
  3. aorto-pulmonary septum

--> https://www.sciencedirect.com/science/article/pii/B9780124017306000120

Valvulogenesis

The cNCC also contribute to the aortic and pulmonary valves, thereby connecting the heart to the vascular system. OFT endothelial cells that have undergone endoMT are thought to give rise to the bulk of the semilunar valves, which form within the aorta and pulmonary artery, to prevent the back flow of blood into the ventricles. In addition, cardiac NCCs also colonize the semilunar valves, where they mainly contribute to the two leaflets adjacent to the aorticopulmonary septum. Cells of the NCC have also been found to contribute to the atrioventricular valves, consisting of the bicuspid(mitral) valve and tricuspid valve, which are located between the upper atria and the lower ventricles.

Atrial and Ventricular Separation

Formation of the Cardiac Ganglia

Cardiac ganglia are made entirely from cardiac crest cells.

"Virtually nothing is known about the factors that control their separation from the cardiac crest forming the aorticopulmonary septum or their condensation as ganglia. However, cardiac crest cells also participate in formation of the nodose ganglion. This is the distal sensory ganglion of the vagus nerve. The nodose ganglion is formed from neurons derived from the nodose placode located dorsal to pharyngeal arches 4/6. Cells migrate from this placode to coalesce with cardiac crest to form the nodose ganglion. Condensation of this ganglion depends on N-cadherin and signaling by Slit/Robo signaling. In cranial crest Slit1/Robo signaling in conjunction with N-cadherin is important for coalescence of crest cells and placode-derived neurons into ganglia. N-cadherin and Robo2 are expressed by placodal neurons and Slit1 is on neural crest cells. If either N-cadherin or Robo2 is knocked down, the ganglia do not coalesce properly.115"

PubmedParser error: Invalid PMID, please check. (PMID: [11])

Signaling Molecules

  1. Wnt: extracellular growth factors that activate intracellular signaling pathways. Decrease of B-catenin results in a decrease in the proliferation of cardiac neural crest cells.
  2. Notch: a transmembrane protein whose signaling is required for differentiation of CNCCs to vascular smooth muscle cells and for proliferation of cardiac myocytes.
  3. BMP (bone morphogenetic proteins): they 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.
  4. FGF8(fibroblast growth factor 8): are essential for regulating the addition of secondary heart field cells into the cardiac outflow tract.
  5. GATA: play a critical role in cell lineage differentiation restriction during cardiac development.
  • Meis2 PubmedParser error: Invalid PMID, please check. (PMID: [12])

Developmental Time Course

Week 3-4 Day 22-28 Neural crest migration starts
Week 5-6 Day 32-37 Cardiac neural crest migrates through the aortic arches and enters the outflow tract of the heart
Week 9 Day 57+ Outflow tract and ventricular septation complete

Human Congenital Heart Diseases associated with Neural Crest Cells

The loss of neural crest cells or their dysfunction may not always directly cause abnormal cardiovascular development, but are involved secondarily because crest cells represent a major component in the complex tissue interactions in the head, pharynx and outflow tract. [1]

Conotruncal Heart Malformations

Persistent Truncus Arteriosus: if the cardiac neural crest is removed before it begins to migrate, the conotruncal septa completely fails to develop, and blood leaves both the ventricles through what is termed a persistent truncus arteriosus, a rare congenital heart anomaly in humans.(Martinson) Failure of outflow tract septation may also be responsible for other forms of congenital heart disease, including transposition of the great vessels, high ventricular septal defects, and tetralogy of Fallot (Martinson).

This is a defect on the NKX2 gene/locus

DiGeorge Syndrome and Velocardiofacial Syndrome

DiGeorge syndrome (DGS) is a condition that affects the development of many tissues that are patterned by or derived from NCCs. Thus, patients have variable types of craniofacial defects, aplasia or hypoplasia of the thymus and parathyroid glands, and OFT and aortic arch defects.(reference here)


  • Caused by a chromosomal 22q11.2 deletion.
  • a hemizygous deletion within chromosome band 22q11.2 has been found in 25% of DGS patients.
  • Characterized by interrupted aortic arch type B, outflow tract malformations that include xxx

[1]

C.H.A.R.G.E Syndrome

  • Coloboma
  • Heart anomaly
  • Atresia of choanae
  • Retardation of physical and mental development
  • Genital hypoplasia
  • Ear anomalies and/or deafness

PubmedParser error: Invalid PMID, please check. (PMID: [13])

The link between the chromatin-remodeling protein CHD7 with cardiac NCC-associated defects suggests that epigenetic regulation is important for genes controlling NCC function.


--> https://pdfs.semanticscholar.org/42cc/ee7fbb545ea6752e1c126cc2769e8e33e7b7.pdf

Mutations in the chromatin helicase DNA-binding protein 7(CHD7) gene are causative of CHARGE syndrome and loss-of-function

Neural crest cells contribute to these deformations and abnormalities of the tissues. How is because NC development involves many convoluted steps such as specification, delaminatoin, migration, induction and differentiation. These processes are controlled by regulatory gene networks. If certain genes are disrupted affecting the neural crest cells then a variety of human diseases arise categorized as neurocristopathies. CHARGE is an acronym for a collection of symptoms including, heart defects,retarded growth and development, genital hypoplasia, ear anomalies and deafness. CHARGE syndrome is a sporadic, autosomal dominant malformation disorder diagnosed in 1/8,500-1/10,000 live births.In addition, malformations of the foregut, kidneys, limbs, lung, and liver have been described in infants with CHARGE syndrome. The gene most commonly affected in patients with CHARGE syndrome is CHD7, which encodes a DNA binding protein involved in chromatin remodeling(reference here).

--> https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.31584

Models and Research

Animal Models

  • Main animal models are chick and mouse.

Research has been done on mouse models where...

Research

  • Can cardiac neural crest cells be used to repair human heart tissue? They are basically neural crest stem cells. In 2005, Tomita transplanted neural crest cells from mammal hearts to the neural crest of chick embryos --> find more research for this
  • What is the contribution of the cardiacNCCs to the myocardium and conduction system of the heart.

Glossary

Number | A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z

References

Odelin G, Faure E, Coulpier F, Di Bonito M, Bajolle F, Studer M, Avierinos JF, Charnay P, Topilko P & Zaffran S. (2018). Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. Development , 145, . PMID: 29158447 DOI.

  1. 1.0 1.1 Keyte A & Hutson MR. (2012). The neural crest in cardiac congenital anomalies. Differentiation , 84, 25-40. PMID: 22595346 DOI.