Signaling and transcriptional networks in heart development and regeneration

Abstract

The mammalian heart is the first functional organ, the first indicator of life. Its normal formation and function are essential for fetal life. Defects in heart formation lead to congenital heart defects, underscoring the finesse with which the heart is assembled. Understanding the regulatory networks controlling heart development have led to significant insights into its lineage origins and morphogenesis and illuminated important aspects of mammalian embryology, while providing insights into human congenital heart disease. The mammalian heart has very little regenerative potential, and thus, any damage to the heart is life threatening and permanent. Knowledge of the developing heart is important for effective strategies of cardiac regeneration, providing new hope for future treatments for heart disease. Although we still have an incomplete picture of the mechanisms controlling development of the mammalian heart, our current knowledge has important implications for embryology and better understanding of human heart disease.

Figure 1.

Major steps in heart development. Diagrams of developing hearts (ventral views) are shown. At the cardiac crescent stage, the two heart fields represent different cardiac precursors. The first heart field (FHF, pink) contributes to the left ventricle (lv), and the second heart field (SHF, blue) contributes to the right ventricle (rv) and later to the outflow tract (ot), sinus venosus (sv), and left and right atria (la and ra, respectively). Days of development for mouse and human are shown below. (From Bruneau 2008, with permission.)

Figure 2.

Transcriptional networks in heart development. A representative transcriptional network is shown. (Adapted from Davidson and Erwin 2006.)

Figure 3.

Patterning the developing heart. In situ hybridization in mouse embryos illustrates the complexity and precision of patterning. Shown are in situ hybridizations for Bmp2 (with expression in atrial precursors at E8.5), Nkx2-5 (expressed in all cardiac cells, at E9.25), Irx4 (expressed in ventricular [lv] but not atrial [a] cells at E9.25), Nppa (with a complex chamber expression pattern at E10.5), and the mutually exclusive pattern of Nppa and Tbx2 (Nppa in chamber myocardium and Tbx2 in AV canal [Venter et al. 2001]) at E9.25 and E9.5. a, atrium; avc, atrioventricular canal; lv, left ventricle; rv, right ventricle; v, ventricle. (Adapted from Bruneau 2003, .)

Figure 4.

Later steps in cardiac morphogenesis. Shown are ventricular septation, atrial septation, and septation of the outflow tracts. ao, aorta; as 1°, primum atrial septum; as 2°, secundum atrial septum, cc, cardiac cushions; ot, outflow tract; pa, pulmonary artery; vs, ventricular septum. Days of development for mouse and human are shown below. (From Bruneau 2008, with permission.)

Figure 5.

Function of a Tbx5 boundary in ventricular septation. (A) Effect of misexpression of Tbx5 on septum formation. Left: diagrammatic representation of the experimental design and resulting phenotype. Right: in situ hybridization for Nppa on sections from wild-type (WT) and Tbx5 misexpression hearts, showing absence of septum formation and expansion of expression of Nppa. (B) Phenotype resulting from deletion of Tbx5 from ventricular myocardium (V-del). Two distinct strategies are shown. Left: Optical projection tomography scans of heart from WT and Tbx5 deletion hearts. Note the lack of septation in the absence of Tbx5. (From Koshiba-Takeuchi et al. 2009, with permission.)

Figure 6.

Strategies for cardiac regeneration. Various strategies that have been suggested are shown, including (A) implantation of in vitro-generated cardiomyocytes, (B) differentiation and implantation of cardiac progenitors, (C) mobilization of endogenous precursors by inductive signals, or (D) direct reprogramming. (From Alexander and Bruneau 2010.)