Lecture 17: cardiogenesis

Question 1

Identify the main anatomical differences between the adult heart in key model organisms.

Answer 1

OrganismAtriaVentriclesCirculationAdvantagesXenopus12Little mixing of oxygenated and deoxygenatedUseful to compare to 4 chambered heartZebrafish11No dual circulation – blood goes directly to gillsShort process but similar to humansDrosophilaSingle tubular heart with valves. Parallels between tubular heart and early stages of human developmentHuman22Dual circulationMouse22Dual circulationSimilar to humans

Question 2

Describe the key morphological steps of heart development in vertebrates.

Answer 2

1 – Cardiac precursor cells found in bilateral populations around the midline

2 – Cardiac precursor cells migrate anteriorly to fuse and form the heart tube

3 – Heart tube undergoes asymmetric bending morphogenesis = heart looping

4 – Heart undergoes maturation – formation of structures required for proper function, valves, septa, trabeculae

Question 3

Recall the embryonic origin of cardiac cells

Answer 3

Cardiac cells specified from mesodermal tissue along the primitive streak (mammals) or embryonic margin (fish) through a combinational morphogen signalling.

FHF -> heart tube, L and R atria, L ventricle

SHF -> L and R atria, L ventricle

Question 4

Describe the mechanisms underlying cardiac specification.

Answer 4

Cardiac precursor cells become either the first heart field or second heart field. Cells receive non canonical Wnt signalling and canonical Wnt signalling is inhibited. Then cells that receive BMP become first heart field cells which migrate anteriorly to form the primitive heart tube. The second heart field cells now receive canonical Wnt signalling and migrate the adjacent mesoderm.

Question 5

Describe heart patterning and the regulation of heart looping. Give experimental evidence for the key genes involved.

Answer 5

The heart needs to undergo functional regionalisation:

• Chamber (contractile myocardium) vs non-chamber (non-contractile)
• Atrial vs ventricular
• Inflow (pacemaker/valves) vs outflow (valves)
• AV canal (AV node/valves)

Patterning begins in the tube stage through two genetic pathways os inhibiting and activating signals:

Chamber structures are patterned through the Notch-TBx20 axis

The AV canal is structured through the BMP-Tbx2 axis.

TBX20 is a TF that represses the AV canal program:

• LOF mutants have no Nppa (chamber-specific) expression and have upregulated TBX2 expression where the chamber should be
• Nppa encodes a protein that controls extracellular fluid volume

TBX2 is a TF that represses the chamber program:

• LOF mutants don’t have specified valves and have too much chamber-specific Nppa expression

Heart Looping Morphogenesis – growth from second heart field cells

• Heart tube buckles driven y asymmetric movement at the poles
• Pushes from either end to form a helical twist (looping) – driven by cells migrating into the heart
• L and R ventricle form as two groups of cells on top of each other
• Regional changes in the ECM
• Asymmetry driven by lateralised cell signalling from the embryo

Question 6

Understand interplay between heart form and heart function during development.

Answer 6

Heart is functional during development so that blood flows through. Blood has a role in spatiotemporal gene expression. These are called flow-responsive genes.

The early heart chambers do not have valves so during contraction, blood regurgitates. The regurgitation influences gene expression by activating KLF2 which triggers valve formation.

Form -> flow -> flow

Growth/patterning/morphogenesis -> allows blood flow -> blood flow drives morphogenesis