Heart development
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The heart is the first functional organ in a vertebrate embryo. There are 5 stages to heart development.
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[edit] Specification of cardiac precursor cells
The lateral plate mesoderm delaminates to form two layers: the dorsal somatic (parietal) mesoderm and the ventral splanchnic (visceral) mesoderm. The heart precursor cells come from the two regions of the splanchnic mesoderm called the cardiogenic mesoderm. These cells can differentiate into endocardium which lines the heart chamber and valves and the myocardium which forms the musculature of the ventricles and the atria.
The heart cells are specified from the anterior endoderm through the BMP and FGF signaling pathways. These signals are necessary and if the anterior endoderm is removed, heart formation is blocked. These signals are sufficient to cause heart differientation and if posterior mesoderm receives signals from the anterior endoderm, the posterior mesoderm is induced to become heart tissue.
The anterior endoderm also secretes Wnt inhibitors (such as Cerberus, Dickkopf and Crescent) which prevent Wnt3a and Wnt8 secreted by the neural tube from inhibiting heart formation. The notocord secretes BMP antagonists (Chordin and Noggin) to prevent formation of cardiac mesoderm in inappropiate places.
These cardiogenic signals (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.
[edit] Migration of cardiac precursor cells and fusion of the primodia
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.
[edit] Heart 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. It is possible that the asymmetry is caused by the clockwise rotation of cilia in dispersing this transcription factor. Looping also depends on heart specific proteins activated by Nkx2.5 such as Hand1, Hand2, and Xin.
[edit] Heart chamber formation
The cell fates of the heart chambers are characterized before heart looping but can not be distinguished until after looping. Hand1 is localized to the left ventricle while Hand2 is localized to the right ventricle.
[edit] Septation and valve formation
Proper positioning and function of the valves is critical for chamber formation and proper blood flow. The endocardial cushion serves as a makeshift valve until then.
