The mechanism that positions the heart on the left

Instituto de Neurociencias de Alicante (IN - CSIC - UMH)

Our bodies show an external bilateral symmetry. However, there are many internal asymmetries. As such, our liver is on the right while the spleen and heart are on the left. During embryonic development, all these organs appear at the midline and later they are displaced to their final position. This process is essential for correct organ packaging and function. The heart must have its posterior pole pointing to the left in order to achieve the proper concordance with the vasculature.

Defects in L/R asymmetry arise in 1/10,000 humans, and the associated morbidity and mortality usually imply congenital heart defects (CHDs). According to data from the World Health Organization, every year more than 250,000 newborns die during the first weeks due to congenital anomalies. The most frequent serious congenital disorders are cardiac malformations, neural tube defects and Down syndrome. 50% of these malformations are cardiac, many of them related to the position of the heart.

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Proposed model for heart looping in vertebrates. NT, neural tube; PP, posterior pole; OFT, outflow tract.

The establishment of left–right asymmetries in vertebrate embryos was thought to depend on a signalling pathway mediated by Nodal–Pitx2 that induces left-side properties. Evidence indicated that right-side properties are specified as a default state, with the Nodal-driven pathway being repressed on the right-hand side by the epithelial–mesenchymal transition (EMT) factor Snail. Angela Nieto and colleagues analysed fish, chicken and mice and found that the normal asymmetric development of their hearts requires the activity of another signalling pathway. This BMP-driven pathway promotes the expression of EMT factors on the right-hand side of the lateral plate mesoderm, which induces cell movements that are necessary for the dextral looping of the heart. The authors of this work conclude that left–right asymmetries in vertebrates are set up by both Nodal- and BMP-driven pathways that are mutually repressed on the opposite side of the developing embryos. Thus, a differential L/R EMT produces asymmetric cell movements and forces, more prominent from the right, that drive heart laterality in vertebrates.

 

Reference:

Oscar H. Ocaña, Hakan Coskun, Carolina Minguillón, Prayag Murawala, Elly M. Tanaka, Joan Galcerán, Ramón Muñoz-Chápuli & M. Angela Nieto; Nature volume 549, pages 86–90 (07 September 2017); doi:10.1038/nature23454

Image credits:

Frontpage image "Heart with coronary arteries", licensed from MedicalGraphics with a creative commons CC BY-ND 3.0 license.

In-text image provided by IN from original research article.

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