Protein signalling in heart development
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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 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 The endocardial tubes are paired regions in the embryo that appear in its ventral pole by the middle of the third week of gestation and consist of precursor cells for the development of the embryonic heart. The endocardial heart tubes derive from t ...
. These cells can differentiate into endocardium which lines the heart chamber and valves and the
myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
which forms the musculature of the ventricles and the atria. The heart cells are specified in anterior mesoderm by proteins such as Dickkopf-related protein 1,
Nodal homolog Nodal homolog is a secretory protein that in humans is encoded by the ''NODAL'' gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta superfamily (TGF-β superfamily). Like many other members of this su ...
, and Cerberus secreted by the anterior
endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...
. Whether Dickkopf-1 and Nodal act directly on the cardiac mesoderm is the subject of research, but it seems that at least they act indirectly by stimulating the production of additional factors from the anterior endoderm. These early signals are essential for heart formation such that removal of the anterior endoderm blocks heart formation. Anterior endoderm is also sufficient to stimulate heart differientation since it can induce non-cardiogenic mesoderm from more posterior positions in the embryo to form heart. 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 . The direction of asymmetry is established much earlier during embryonic development, possibly by the clockwise rotation of
cilia The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...
, and leads to sided expression of Pitx2. Looping also depends on heart specific proteins activated by Nkx2.5 such as , , and Xin. 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 endocardial cushion serves as a makeshift valve until then.


Step 3(a): Atrial septation

The primitive atrium is divided in two by joining of several structures. From the roof of the primitive atrium descends the septum primum, which grows towards the endocardial cushions within the atrial canal. Right before the septum primum fuses with the endocardial cushions there's a temporary space called the foramen primum. Once they fuse a new opening forms in the middle of the septum primum called the ostium secundum or ''foramen secundum''. To the right of the septum primum and also coming down from the roof of the primitive atrium, descends a semilunar-shaped partition called the septum secundum. The free edges of the septum secundum produce an orifice called ''
foramen ovale There are multiple structures in the human body with the name foramen ovale (plural: ''foramina ovalia''; Latin for "oval hole"): * Foramen ovale (heart), in the fetal heart, a shunt from the right atrium to left atrium * Foramen ovale (skull), at ...
'', which closes after birth when the septum primum and secundum fuse to each other completing the formation of the atrial septum. 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 endocardial cushion. The right side of the atrial canal will become the tricuspid valve and the left will become the
bicuspid valve The mitral valve (), also known as the bicuspid valve or left atrioventricular valve, is one of the four heart valves. It has two cusps or flaps and lies between the left atrium and the left ventricle of the heart. The heart valves are all one-w ...
. Defects in producing the AV septum produces atrioventricular septal defects, including a persistent AV canal and
tricuspid atresia Tricuspid atresia is a form of congenital heart disease whereby there is a complete absence of the tricuspid valve. Therefore, there is an absence of right atrioventricular connection. This leads to a hypoplastic (undersized) or absent right ventri ...
.


Step 3(b): Ventricular septation

The floor at the midline of the primitive ventricle produces the interventricular septum, separating the chamber in two. The IV septum grows upward towards the endocardial cushion. As it grows, a foramen appears, the interventricular foramen, which later is closed by the non-muscular IV septum. 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. 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 The aorticopulmonary septum is developmentally formed from neural crest, specifically the cardiac neural crest, and actively separates the aorta and pulmonary arteries and fuses with the interventricular septum within the heart during heart develop ...
. This will end dividing the aorta from the pulmonary trunk. Defects in this process is known as
aortopulmonary septal defect Aortopulmonary septal defect is a rare congenital heart disorder accounting for only 0.1-0.3% of congenital heart defects worldwide. It is characterized by a communication between the aortic and pulmonary arteries, with preservation of two normal s ...
, and causes
persistent truncus arteriosus Persistent truncus arteriosus (PTA), often referred to simply as truncus arteriosus, is a rare form of congenital heart disease that presents at birth. In this condition, the embryological structure known as the truncus arteriosus (embryology), t ...
, unequal division of the truncus arteriosus, transposition of the great arteries,
aortic The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ox ...
and pulmonary valve stenosis or tetralogy of fallot.


Step 5: Heart valve formation

The heart valves are formed. Defects in this process are known as valvular heart disease.


References

{{Development of circulatory system


External links


Cardiac Embryology Interactive 3D Module (Flash Player 10 required)
* ]http://php.med.unsw.edu.au/embryology/index.php/Cardiac_Embryology Cardiac embryology] at
UNSW The University of New South Wales (UNSW), also known as UNSW Sydney, is a public research university based in Sydney, New South Wales, Australia. It is one of the founding members of Group of Eight, a coalition of Australian research-intensive ...
Embryology of cardiovascular system