Protein signalling in heart development
The heart is the first functional organ in a vertebrate embryo. There are 5 stages to heart development.
Stages of heart development
Initiation
Specification of cardiac precursor cells: The
The heart cells are specified in anterior mesoderm by proteins such as
The secretion of Wnt inhibitors (such as Cerberus, Dickkopf and Crescent) by the anterior endoderm also prevents Wnt3a and Wnt8 secreted by the neural tube from inhibiting heart formation. The notochord secretes BMP antagonists (Chordin and Noggin) to prevent formation of cardiac mesoderm in inappropriate places.
Other cardiogenic signals such as BMP and FGF activate the expression of cardiac specific transcription factors such as homeodomain protein Nkx2.5. Nkx2.5 activates a number of downstream transcription factors (such as MEF2 and GATA) which activate the expression of cardiac muscle specific proteins. Mutations in Nkx2.5 result in heart development defects and congenital heart malformations.
Step 1: Tube formation
Migration of cardiac precursor cells and fusion of the primordia: The cardiac precursor cells migrate anteriorly towards the midline and fuse into a single heart tube. Fibronectin in the extracellular matrix directs this migration. If this migration event is blocked, cardia bifida results where the two heart primordia remain separated. During fusion, the heart tube is patterned along the anterior/posterior axis for the various regions and chambers of the heart.
The surrounding mesocardium degenerates to leave the primitive heart attached only by its arterial and venous ends, which are anatomically fixed to the pharyngeal arches and the septum transversum, respectively. The developing tubular heart then folds ventrally and bulges in five regions along its length: the first one and closest to the arterial end is the truncus arteriosus, then follow the bulbus cordis, the primitive ventricle, the primitive atrium and the sinus venosus. All five embryonic dilatations of the primitive heart develop into the adult structures of the heart.
Step 2: Looping
The heart tube undergoes right-ward looping to change from anterior/posterior polarity to left/right polarity. The detailed mechanism is unknown however the looping requires the asymmetrically localized transcription factor Pitx2. The direction of asymmetry is established much earlier during embryonic development, possibly by the clockwise rotation of
Heart chamber formation: The cell fates of the heart chambers are characterized before heart looping but cannot be distinguished until after looping. Hand1 is localized to the left ventricle while Hand2 is localized to the right ventricle.
Step 3: Septal formation
Proper positioning and function of the valves is critical for chamber formation and proper blood flow. The
Step 3(a): Atrial septation
The
The atrial canal is in turn divided into a right and left side by the atrioventricular septum, which originates from the union of the dorsal and ventral
Defects in producing the AV septum produces atrioventricular septal defects, including a persistent AV canal and tricuspid atresia.
Step 3(b): Ventricular septation
The floor at the midline of the
Defects in producing the IV septum causes ventricular septal defects, which communicate both ventricles.
Step 4: Outflow tract septation
The truncus arteriosus and the adjacent bulbus cordis partition by means of cells from the neural crest.[1] Once the cells from the truncal ridge meet with the cells from the bulbar ridge they twist around each other in a spiral orientation as they fuse and form the aorticopulmonary septum.[2] This will end dividing the aorta from the pulmonary trunk.[3]
Defects in this process is known as
Step 5: Heart valve formation
The
Defects in this process are known as valvular heart disease.