Fig. 7. Myocardial Bmp2 gain promotes ectopic EMT, stimulates cardiac proliferation and disrupts ventricular patterning and cardiomyocyte maturation.

a Left, E9.5 WT heart, chamber (ventricles and atria, green and light green) and non-chamber myocardium (AVC, blue) are specified. Bmp2 expression in AVC myocardium drives EMT via Twist1, Snail and Slug activation in AVC endocardium (purple). The Irx5-positive ventricular endocardium is coloured in red and the atrial endocardium in yellow. Right, E14.5 WT heart, the compacting ventricular myocardium is formed by an outer compact myocardium (Hey2-, n-Myc-positive, light green) and an inner trabecular myocardium (Bmp10-, Cx40-, Sema3a-positive, dark green). Tbx20 is expressed in compact and weakly, in trabecular myocardium. The maturing AVC valves (blue) express Bmp2 and Tbx2. B; left, E9.5 Nkx2.5^Cre/+(or cTnT^Cre/+);Bmp2^tg/+ transgenic heart. Bmp2 is normally expressed in AVC myocardium (blue) and ectopically in ventricular myocardium (light blue), driving Twist1, Snail and Slug expression in the Irx5-negative ventricular endocardium (purple), causing ectopic EMT. Right, E14.5 Nkx2.5^Cre/+(or cTnT^Cre/+);Bmp2^tg/+ transgenic heart. Bmp2 is expressed in an expanded AVC valve region (blue) and throughout the ventricles (green), leading to increased and expanded Tbx20, Hey2, n-Myc and Id2 expression in this tissue. As a consequence, cardiomyocyte proliferation is increased and chamber patterning/maturation is disrupted. The discontinuous arrow represents a potential positive feedback loop between Tbx20 and Bmp2 and the suggested negative regulation of Tbx2 by Tbx20 and Hey2. The asterisk indicates a ventricular septal defect. Abbreviations as in Fig. 1