What is the OFT separated into?
What spirals in a downward motion during separation?
- A single tube (labelled bulbus and conus in this diagram) is separated into the aorta and pulmonary artery
- These must be attached to the left and right ventricles, respectively
- Two cushions spiral through the truncus arteriosus
What gives rise to the the aortic arch?
- The truncus arteriosus is connected into the aortic arteries which are symmetrical in transient structure from the pharyngeal arches. They form in a sequence from the anterior to posterior direction. As the 4th arch artery starts to form the 1st will degenerate. As the 5th arch artery starts to form (labeled 6) the 2nd arch artery will degenerate. So we are left with 3 symmetrically paired pharyngeal arch arteries running through the center of each of the phalangeal arches. They will be remodeled to give rise to structures within the aortic arch.
How is the OFT separated?
- In order for the truncus arteriosus to be separated: it will occur via cushion forming on the inside of the trunk and will spiral down in towards the heart and will be joined correctly at the AV junction and distally into the aortic arch arteries.
How do the neural crest cells separate the outflow tract?
- The cells responsible for the separation of the outflow tract are the cardiac neural crest cells. They have arisen from the neural tube. Before the neural tube fuses at the dorsal surface a small group of cells on either side of the embryo migrate away from the dorsal neural tube and some migrate through the pharyngeal arches surrounded the pharyngeal arteries down into the outflow tract.
- The migrating cardiac neural crest cells will populate the outflow tract and will divide the tract, dividing it into the aorta and pulmonary artery. As this happens they cause changes in blood flow on the left and right side of the common trunk. The changes in blood flow results in the degermation of the aortic arch arteries on the left and right side.
- We can see where each aortic arch artery will give rise to in the adult
Describe the movement of the cushions through the outflow tract
- The pulmonary artery will need to connect to the right ventricle and the aortic artery will need to connect to the left ventricle
- The common outflow tract: the truncus arteriosus has two spiraling cushions going down through it, where it starts distally and moves proximally.
- The spiraling cushion creates a differential blood flow within the common trunk from the left and right hand side. The spiral cushions are populated primarily from cardiac neural crest cells and will form the aortic and pulmonary septum.
- The spiraling arrangement within the common arterial trunk that will be remodeled to give 2 vessels
- The cushions alter how blood is moving through the symmetrical aortic arches on each side and will lead to the degeneration or persistence of aortic arches depending on the position of the spiraling cushion
Describe the re-organisation of the aortic arches?
- Aortic arches undergo complex remodeling and will join precisely with the AV septum, to partition between the left and right ventricles.
- The 6th arch artery gives rise on the left hand side to the ductus arteriosus which allows the fetal circulation to bypass the lungs. After birth the ductus arteriosus is closed to form the ligamentum arteriosum.
- As the cushions spiral into the proximal region of the heart they will fuse with the AV septum and IV septum to separate the four chambers.
How can we label neural crest cells?
- Lineage labelling by Wnt1-Cre (marker of neural crest) crossed to lacz-R26R
- Cardiac NCC shown in the heart at E12.5
What is Transposition of the great arteries (TGA)?
- Aorta connected to right ventricle
- Pulmonary trunk connected to left ventricle
- Arterial trunks usually side-by-side
- Probably caused by abnormal outflow tract cushions
- Lethal without VSD, ASD or PDA (shunting of blood from the right side to the left side of the heart)
- Cyanotic
How is TGA surgically corrected?
Arterial switch – spiralling the pulmonary artery into the right atrium and the aorta into the left ventricle
Atrial switch – the right atrium is now diverted into the left ventricle and the left atrium is diverted into the right ventricle pumping into the systemic circulation.
What are the characteristics of the tetralogy of fallot?
Four characteristic features: • VSD (large) • Pulmonary stenosis • Right ventricular hypertrophy • Overriding aorta
- Right>Left shunt
- Cyanotic
- Complex phenotype may result from abnormal looping, leading to malalignment of segments
What does squatting do in tetralogy of fallot?
- Squatting increases peripheral arterial resistance and causes a left to right shunt
- Increases pulmonary blood flow
What does the SAN do?
- The sinus atrial node on the right atrium relays its signals through the atrial walls to the AVN found at the junction between the atria and the ventricles
- This signal is then relayed via purkinje fibres down towards the apex of the heart where the heartbeat is initiated and up through the ventricles walls
What does cardiac conduction tissue come from?
Give an electrical insulation layer
What are the Ventricular bundle branches wrapped in and what does this do?
• Conduction tissue is specialized myocardium, not nerves (they come from neural crest cells)
• Variations in conduction properties caused by differences in ion channel and connexin (gap junctions) expression that creates pores between adjacent cells
• Conduction system differentiates by progressive, localised recruitment from heart tube myocardium
• Electrical insulation layers:
o Fibro-fatty layer at AV junction (from cushions)
o Ventricular bundle branches wrapped in a fibrous sheath so you don’t initiate contraction along the intraventricular septum
How does the heart form compact and trabecular layers?
- The ventricle walls will develop to form finger like projections, they become more define and more organised
- We have proliferating cardiomyocytes on the outside of the heart and more differentiated cardiomyocytes moving inwards (shown in red). The lines represent the extracellular matrix and then endocardial cells on the inside of the heart. The formation of the finger like projections is driven by Notch
- The trabecular growth won’t proceed until the epicardial cells shown in green start to surround the outside of the heart. This growth is driven by BMP10 and ephrin
- The collaboration between the trabeculae is driven by the epicardium which differentiate into endothelial cells shown in yellow (coronary vasculature). FGF and Shh is involved.
- The differentiated cardiomyocytes become more organised which is driven through the planar cell polarity pathway.
How is the epicardium formed?
- Epicardium is formed from the proepicardial organ
- PEO cells shown migrating onto the myocardial heart tube and spreading to envelope it
- The PEO cells start to migrate out, they attach to the heart tube and proliferate and spread over the surface of the heart and will cover the entirety of the heart. These cells make up the epicardium.
- These are images from the chick
- In mammals, some PEO cells free-float onto the tube.
What is the proepicardial organ found upon?
What do some epicardial cells form?
What factors are required for epicardial development?
Does the epicardium produce signals that control that controls myocardial development and proliferation?
What is a key regulator of epicardial formation?
- The epicardium is produced almost all from the proepicardial organ on the septum transversum
- Epicardial-derived cells make the coronary vessels, some nerves, some myocardium and may contribute to valves
- RALDH2, RARs, Wt1 and FOG2 required for epicardial development
- The epicardium produces signals that control myocardial development and proliferation
- Recently, thymosin B4 has been shown to be a key signal: a key regulator of epicardium formation
What is the function of Thymosin-beta 4?
What happens in a TB4 knockout?
- On the left is a section of the ventricular wall showing the a single epithial layer of epicardial cells surrounding the myocardium of the heart. It is first compact on the outside and forms trabecular layes moving inwards. The epithelial cells of the epicardium undergo an EMT trnaistion to give rise to epicardial progenitor cells (these cells start to express TB4). They then go on to form angiogenic cells (cells that express the receptor type: Tie2 which will form coronary vasculature which then become surrounded by smooth muscle cells which are also derived from epicardium cells. The smooth muslce cells then surround the endothelial cells to give us functional blood vessels.
- In a TB4 knock out mouse this process down not occur normally. Although the vessel walls will form, they are not as well formed and don’t progress and begin to regress. So the blood vessels don’t form. The smooth muscle cells cannot then surround the vascukature. On the myocardium the compacted layer doesn’t expand fully and the trabecular layer is also disorganised.
What does the ballooning model state?
- The primary heart tube (grey) is “primitive”, with slow conduction
- Some regions retain their primary character
- The chambers (blue) balloon from the primary tube, and acquire working characteristics, like fast conduction
What key transcription factors are expressed in the heart
What is the chamber myocardium marked by?
What forms the primary myocardium?
• Expressed in partly overlapping domains
• In combination, they specify different regions of the heart tube
• Tbx genes are particularly important
1. This is a newly formed heart tube. These genes specify different regions of the heart.
2. The chamber myocardium is marked by NKX2.5 and GATA4 and tbx5 in the chambers. The grey regions also express tbx2/3 to form primary myocardium
Where is ANF initially expressed?
What does ANF expression do?
What then expresses ANF?
What does not express ANF?
- We can see specification of different regions of the heart using ANF, which is intially expressed in the forming ventricles, the blue region then expressed ANF.
- ANF expression increases in the ventricular region. The atrial region also starts to express ANF to form the atria.
- The AVC is not expressing ANF nor it the outflow tract.
Describe the local repression of genes to form the ventricles and atrium
On image
What transcription factor induces formation of the chambers, conduction system, inflow and outflow region?
On image
What represses ANF in the AV canal and OFT?
• Based on the view that a key difference between regions of the heart is in electrical conduction function
• The primary myocardium of the early heart tube has slow conducting properties
• Some regions retain this “primitive” feature
o Due to Tbx 2 & 3 mediated repression, there is no induction of ANF
o The final conduction system is one derivative of primitive myocardium
• Other regions become chamber (or working) myocardium, e.g. ventricles and atrial appendages
• These regions form by ballooning, away from the primitive tube
o At least in part induced by Tbx5: express ANF, Cx43, chisel, lrx5
• Tbx 2&3 and ANF/Cx43 expression mutually exclusive
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The concepts and language of development54
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Animal Models in Development19
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Methods in Development35
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Signalling Pathways42
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Primary Cilla, signalling and development21
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Genome editing and sophisticated transgenesis59
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Neurulation42
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Boundary Formation41
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Somitogenesis34
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Organoids and stem cells30
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Eye development39
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Ear development35
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Neural Crest Part 126
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Neural crest part 217
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Heart development46
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Heart Development Part 223
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Limb Development54
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Limb Development Part 210
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Cortical Development53
