Tgf signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development

The transforming growth factor (Tgf) signaling pathway plays crucial roles in many biological processes. To understand the role(s) of Tgf signaling during cardiogenesis in vivo and to overcome the early lethality of Tgfbr2^-/- embryos, we applied a Cre/loxp system to specifically inactivate Tgfbr2 in either the myocardium or the endothelium of mouse embryos. Our results show that Tgfbr2 in the myocardium is dispensable for cardiogenesis in most embryos. Contrary to the prediction from results of previous in vitro collagen gel assays, inactivation of Tgfbr2 in the endocardium does not prevent atrioventricular cushion mesenchyme formation, arguing against its essential role in epithelium-mesenchyme transformation in vivo. We further demonstrate that Tgf signaling is required for the proper remodeling of the atrioventricular canal and for cardiac looping, and that perturbation in Tgf signaling causes the double-inlet left ventricle (DILV) defect. Thus, our study provides a unique mouse genetic model for DILV, further characterization of which suggests a potential cellular mechanism for the defect.