Introduction

Heart development, or cardiogenesis, is the process by which the heart develops from the earliest specification of cardiac cells to the final four chambered heart, pumping blood through the body. Heart development is a complicated process; it requires the coordination of all three body axes to create a complex 3-D shape as well as precise timing and specificity of transcription factors and signalling molecules.

Cardiac Cell Populations

There are four chief cardiac cell progenitor populations: the first heart field (FHF), the secondary heart field (SHF), the cardiac neural crest cells (cNCCs) and the proepicardium.  The table below gives key details about their origins, their derivatives and some of the signalling molecules and pathways involved in their function and development.

Heart Morphogenesis

All cardiac progenitor cells originate from mesodermal cells formed in the anterior region of the primitive streak of the embryo. At embryonic day (E) 7.5, after initial cardiac induction has taken place, the FHF and SHF migrate and expand across the midline of the embryo to form the linear heart tube, which begins to beat. At this point chamber specification has been determined already. The SHF migates onto the beating linear heart tube at E8.5 during heart looping.

Heart Looping

At E8.5 the linear heart tube 'loops' dextrally to correctly align the atria and ventricles relative to each other. This is the first physical instance of left-right asymmetry in the embryo. Most of the research on the physical process of heart looping has been carried out using chick embryos. This research showed that there are two stages to heart looping; the 'C' stage and the 'S' stage. In the simplest terms, during the 'C' phase the linear heart tube bends and twists to assume a 'C' shape pointing towards the right of the embryo. In the later 'S' stage the atria move so that they are anterior relative to the ventricles. Septation then separates the chambers.

Maturation

At E9.0, once heart looping is complete, the proepicardium migrates onto the heart. By E11, the proepicardium has completely enveloped the heart tube and formed the epicardium, a sheet of epithelial cells. At the same time, the cardiac neural crest cells invade the outflow tract of the developing heart from the dorsal neural tube where they help form the aroticopulmunary septum and great vessels, among other structures. The chambers of the heart assume the correct morphology and their walls thicken.

Early Cardiogenic Signalling Molecules

Heart development is controlled by important signalling molecules and transcription factors, many of which are well characterised.  Some of these, such as bone morphogen protein (BMP) signalling and Wnt signalling are widely used signal transduction pathways in embryogenesis. Others, such as the transcription factors GATA4 and Nkx2-5 are specifically involved in cardiogenesis and may have no other function.

 

BMP and Wnt signalling

  • Cardiac induction is first determined by BMP and Wnt signalling
  • BMP signalling induces cardiogenesis; the loss of BMP receptor 1a completely prevents formation of the FHF.
  • Wnt signalling has a complex role in cardiogenesis. Initially it had been suggested that canonical Wnt/beta-catenin signalling inhibits cardiogenesis and non-canonical Wnt signalling promotes it. However, it has since been shown that canonical Wnt signalling is needed to regulate BMP4 and so control proliferation of Isl-1 expresssing cells in the SHF.

 

GATA4:

  • One of the earliest cardiac markers.
  • Activated by BMP signalling and regulates the expression of structural genes as well as other downstream transcription factors involved in heart development.
  • It is essential for cardiac crescent folding; 'knocking out' GATA4 results in cardia bifida.
  • GATA4 is not essential for cardiomyocyte differentiation, possibly indicating that other GATA transcription factors can compensate for its loss.

 

Nkx2-5:

  • Essential for proper development of both the FHF and SHF.
  • Promotes expression of cardiogenic genes and interacts with transcription factors.
  • Involved in the development of the myocardium and yolk sac vasculature.
  • Also influences heart looping and controls ventricular gene expression.
  • Activated by GATA4 and is under the control of BMP signalling, which Nkx2-5 itself downregulates.

 

 

A vast number of other genes and transcription factors are involved in cardiogenesis.  These include Mef2c, which is needed for differentiation of cardiac muscle tissue. Several T-box (Tbx) genes are needed for cardiogenesis, particularly Tbx2, 3, 5 and 20 which are involved in formation of the cardiac conduction system and the ventricles. The genes Hand1 and 2, which are basic helix-loop-helix transcription factors, are important in the development of the left and right ventricle respectively. Animals with only one ventricle, such as zebrafish, have only one Hand gene.

      Human Congenital Heart Disease (CHD)

      CHD affects 1-2% of all human live births and is the most common cause of non-infectious neonatal death. Treatment of CHD requires major surgery and quality of life is often negatively affected despite treatment.

      CHD has been linked to single gene mutations in many genes involved in cardiogenesis; mutations in the gene Tbx5 cause Holt-Oram syndrome, which frequently results in limb abnormalities and atrioventricular septation defects.  Mutations in the Nkx2-5 gene, which could be expected to completely prevent cardiogenesis, typically results in septal defects and conduction abnormalities.

      References

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      Brown, C, O., Chi, X., Garicia-Gras, E., Shirai, M., Feng, X-H. and Schwartz, R, J. (2004) The Cardiac Determination Factor, Nkx2-5, Is Activated by Mutual Cofactors GATA-4 and Smad1/4 via a Novel Upstream Enhancer. J. Biol. Chem. 279(11):10659-69

       

      Garg, V., Kathiriya, I, S., Barnes, R., Schluterman, M, K., King, I, N., Butler, C, A. and Rothrock, C., R. et al (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443-447

       

      Klaus, A., Saga, Y., Taketo, M, M. Tzahor, E. and Birchmeier, W. (2007) Distinct roles of Wnt/B-catenin and Bmp signaling Kodo, K. and Yamagishi, H. (2011) A Decade of Advances in the Molecular Embryology and Genetics Underlying Congenital Heart Defects. Circ. J. 75:2296-304

       

      Nemer, M. (2008) Genetic insights into normal and abnormal heart development. Cardiovascular Pathology. 17(1):48-54

       

      Prall. O, W, J., Menon, M, K., Solloway, M, J. Watanabe, Y, Zaffran, S., Bajolle, F., Biben, C., McBride, J, J. and Harvey, R, P. et al (2007). An Nkx2-5/Bmp2/Smad1 Negative Feedback Loop Controls Heart Progenitor Specification and Proliferation. Cell 128(5):947-959

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