Lecture 17- Heart development Flashcards
What is congenital heart disease?
Structural malformations due to the heart not developing properly during embryogenesis
Give 3 examples of organisms with a similar 4 chambered heart
Human, mice, chicks
Describe the heart structure in xenopus
3 chambered heart
Describe the heart structure in zebrafish
2 chambered heart for a single circulatory system
Describe the heart structure in drosophila
Tubular heart with an enlarged vessel with valves to ensure unidirectional flow
Outline the 4 key morphological steps in heart development
- Cardiac precursor cells found as BILATERAL POPULATIONS of cells around the midline
- Migrate to the midline and fuse to form the HEART TUBE
- Heart tube undergoes an asymmetric bending morphogenesis termed HEART LOOPING
- The heart undergoes MATURATION, resulting in formation of structures required for proper function – valves, septa, trabeculae
Describe the cardiac crescent
A bilateral population of cells which span across the embryos midline and comprises of cardiac precursors
Describe the formation of the heart tube
The migration of cells and fusion of cells at the midline
Define heart looping/loop morphogenesis
Heart tube undergoes asymmetric bending and ballooning
What if formed during heart maturation?
Forming valves between chambers, and connecting to surrounding vasculature
Why does the heart undergo looping?
Reorganising the heart chambers so structures are situated in the correct place and connect properly during maturation
What are the two populations of cardiac cells and which are specified first?
- First heart field - initially incorporated
2. Second heart field - incorporated later
Where are cardiac cells specified in the mouse and the fish?
Mouse- primitive streak
Fish- embryonic margin
What signalling is required for the initial specification of the cardiac mesoderm?
Non canonical Wnt signalling
What signalling is required to specific FHF and SHF progenitors?
FHF requires BMP
SHF requires canonical Wnt signalling
Once specified, describe the migration of FHF and SHF cells
They migrate anteriorly to form the primitive heart tube (FHF) and SHF in the adjacent mesoderm
What factor does both FHF and SHF cells express?
Nkx2.5
In which ways do cells need to be specified in the heart?
Specify chamber vs non-chamber (e.g. contractile vs non-contractile myocardium)
Chamber cells are then specified into atrial vs ventricular contractility (directional conduction)
Non-chamber cells are specified by inflow (pacemaker/SA node), atrioventricular canal (valve/ AV node), outflow (valves)
What interaction promotes the specification of the AVC?
BMP2-Tbx2
What interaction promotes the specification of of chamber formation?
Notch-Tbx20
Which myocardium does and does not expand during development?
Non-chamber myocardium does not expand during development
Chamber myocardium expands during development to form chambers
Describe the morphology of a Tbx2 mutant mouse and what can be concluded?
Abnormal valve morphology and Nppa expression (chamber marker). They have elongated and non-restricted AVCs
Tbx2 required to promote the AVC programme and also required to inhibit chamber formation
Describe the morphology of a Tbx20 mutant mouse and what can be concluded?
A loss of chamber identity (very small dysmorphic chambers), and an expansion of valve markers (Tbx2).
Informs us Tbx20 is required for the formation of chambers and inhibits the expression of Tbx2
Describe the morphology of a BMP mutant mouse and what can be concluded?
Have defective AVC development similar to Tbx2 mutants
BMP2 mutants have loss of Tbx2 expression therefore BMP2 must be regulating Tbx2 expression
What is the relationship between Tbx20 and Tbx2?
Tbx20 represses Tbx2
What intrinsic process coordinate heart looping morphogenesis?
- Changes in cell shape
- Growth of the heart tube
- Asymmetric cell movements at the poles of the heart
- Regional changes in ECM composition
- Lateralized cell signaling from the embryo
How experimentally can looping morphogenesis be observed in zebrafish?
Using a Tg(myl7:eGFP) which stains myocardial cells green
What promotes looping morphogenesis?
Growth of the heart through the addition of SHF
During heart looping morphogenesis, what happens to the cells on the inner curvature?
Stay cuboidal
During heart looping morphogenesis, what happens to the cells on the outer curvature?
Grow and elongate causing a change in the orientation
Where is Islet1 expressed and how can this be observed experimentally?
Expressed in SHF cells in the mesoderm adjacent to the heart
Observed using mRNA ISH analysis
Where is FGF10 expressed and how can this be observed experimentally?
Expressed in the pharyngeal mesoderm and weakly in the OFT and parts of the right ventricle in the heart
Observed using mRNA ISH analysis
What does lacZ lineage tracing of Islet1 expressing SHF cells show?
That the cells end up in the heart itself
What is observed in mRNA ISH analysis of myl7 in islet1 mutant mice?
The heart is reduced in size and is incompletely
What impact does heart looping being asymmetric mean?
Leaves the heart with inherent asymmetries within the heart tube itself
What 3 things generate organ asymmetry?
Node, nodal flow and nodal
Give 2 examples of diseases associated with L/R heart asymmetry abnormalities?
- Situs inverus
2. Situs ambiguous
When are where is nodal expressed?
Asymmetrically expressed in the left lateral plate mesoderm of embryos prior to organ formation
What does loss of nodal function result in?
Disrupted organ asymmetry
What is the node and what is its role?
- The node is a transient cup-shaped organ which forms during early somitogenesis at the posterior of the embryo
- Lined with motile cilia, which beat in a clockwise movement and creates a directional fluid flow
- Results in elevated calcium in the left side of the embryo
- Elevation of calcium helps to facilitate the transfer of Nodal expression around the Node and into the lateral plate mesoderm on the left of the embryo
Describe the process of asymmetry in the development of the heart
- Asymmetric expression of Nodal: Spaw propagates its expression in the left lateral plate mesoderm
- Asymmetric gene expression in organ anlage: Nodal target genes are expressed in the left half of the cardiac disc
• Asymmetric movement of cells to form the heart tube: cardiac disc undergoes rotation and involution to form tube
Describe the effects of randomised lateralised gene expression in organ laterality in humans
Lead to individuals with mutation in ciliary genes which cause primary ciliary dyskinesia (directional fluid flow is lost) also exhibit heterotaxy
Describe the effects of randomised lateralised gene expression in organ laterality in fish
disruption to KV form or function results in randomisation of spaw expression and directional heart displacement
Describe the effects of lateralised gene expression absence in heart development in humans
Loss of asymmetric gene expression results in disruption to the direction of heart looping
Describe the effects of lateralised gene expression absence in heart development in fish
Identification of Nodal variants in individuals with heterotaxy and isolated cardiovascular malformations due to loss of asymmetric gene expression function
Give 2 examples of sources of mechanical force in the developing heart
Cardiac contractility and cardiac function/blood flow
Why is blood flow important in heart development?
Important for spatiotemporal gene expression of e.g. forming valves. This occurs through flow-responsive genes
Give an example of a flow-responsive gene
Klf2
How does blood flow change under heart morphogenesis?
The greater the morphological the changes are, the more the blood flow route/direction will change
