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Development of the Heart and Regulation of Heart Symmetry Heart development starts with the formation of a symmetric cardiac crescent around the primitive node, towards the cranial end of the lateral plate mesoderm, at around 19 days post-conception in humans. This can be regarded as the primary heart field and contains specified cardiogenic cells. The secondary heart field is marked by Fgf10 and Isl1 expression, and lies medial to the crescent; it will contribute cardiac precursor cells to the heart tube. During lateral folding of the embryo plate around days 20 and 21, the two sides of the cardiac crescent are brought together and form two homologous endocardial tubes, which fuse to form a primitive heart tube. Development of differing heart chamber structures occurs along the heart tube cranial-caudal axis (moving caudally: the conotruncal segment or outflow tract, the bulbus cordis (future right ventricle), the primitive ventricle (future left ventricle), the primitive atria, and the sinus venosus (future venae cavae), each separated by sulci. The heart tube starts to beat 22 days p.c., and undergoes much consecutive bending and folding to form the final structure of the heart. This forms a C shaped structure, with the ventral surface twisting round to form the right surface and much of the dorsal surface becoming the left side. Proliferation of the secondary heart field results in elongation of the cranial and caudal ends, forming an S shaped structure. The result of this process is that the bulbus cordis bulges ventrally, caudally and to the right during folding, to position the right ventricle on par with the left ventricle, which itself is displaced to the left whilst the lower half of the heart tube bends back upwards cranially and dorsally to orient the atria above the ventricles. The outflow tract is also remodelled so that it lies between the two presumptive atria, and splits into the conus arteriosis and truncus arteriosus, respectively to become the outflow parts of the ventricles and the aorta and pulmonary trunk. Once the four chambers have been positioned, heart development continues with the formation of various septa and endocardial cushions which grow and fuse to separate the chambers. All this results from a very complex interplay of factors such as those from the NKX, GATA, and Irx families. The right and left sides of the heart display asymmetric differences which arise during embryonic development, e.g. thicker left ventricle wall, different adjacent vessel structures. The looping of the heart tube is a major embryological event as it is the first instance of asymmetric development, and correct looping is all the more important when one considers that the heart tube must continue beating throughout in order to ensure nutrient and oxygen supply to the embryo. For correct looping and chamber positioning to occur, the heart must develop along a left-right axis (as well as along its other axes), which is established by a combination of asymmetrically expressed factors, secondary heart field action and neural crest cell migration. However these also build upon a left-right gradient previously established in the embryo by notochord expression. Because of the directions the heart tube loops in, left-right axis formation in the heart tube is especially important as it also determines the dorsal-ventral axis in the heart. The absence of a left-right gradient is called heterotaxy and means that the heart cannot loop in the proper directions, or does so only at random; this can lead to dextrocardia (a right-sided left ventricle) and means proper septation cannot occur. It can also lead to isomerism, where two heart chambers have the same sided morphology e.g. two right atria 1. Some factors which play a role in the control of heart development are NKX genes, GATA transcription factors, Irx4 and retinoic acid. NKX2.5 in humans is active in precardiac tissues in the lateral plate mesoderm, implicating a role in cardiac cell commitment. However it cannot induce ectopic hearts alone, and has other roles: hearts fail to loop in NKX2.5deficient mice, and homozygous mutations in humans usually results in atrial septum defects4. Retinoic acid is partially responsible for the cranial-caudal axis in the heart tube, as its presence 'atrialises' tissue which would otherwise form ventricles; this has been demonstrated by artificial addition of RA during chick and mouse cardiogenesis 1,5. Gata4 has been implicated in ventral migration and null mutations lead to abnormal embryonic ventral
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