transforming-growth-factor-beta and Endocardial-Cushion-Defects

The proper formation and function of the vertebrate heart requires a multitude of specific cell and tissue interactions. These interactions drive the early specification and assembly of components of the cardiovascular system that lead to a functioning system before the attainment of the definitive cardiac and vascular structures seen in the adult. Many of these adult structures are hypothesized to require both proper molecular and physical cues to form correctly. Unlike any other organ system in the embryo, the cardiovascular system requires concurrent function and formation for the embryo to survive. An example of this complex interaction between molecular and physical cues is the formation of the valves of the heart. Both molecular cues that regulate cell transformation, migration, and extracellular matrix deposition, and physical cues emanating from the beating heart, as well as hemodynamic forces, are required for valvulogenesis. This review will focus on molecules and emerging pathways that guide early events in valvulogenesis.

Topics: Activin Receptors; Animals; Chick Embryo; Endocardial Cushion Defects; Extracellular Matrix; Fetal Proteins; Gene Expression Regulation, Developmental; Growth Substances; Heart Septum; Heart Valves; Humans; Macromolecular Substances; Mesoderm; Mice; Mice, Knockout; Morphogenesis; Receptors, Growth Factor; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

The transforming growth factorbeta (Tgfbeta) signaling pathway plays crucial roles in many biological processes. To understand the role(s) of Tgfbeta 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 Tgfbeta signaling is required for the proper remodeling of the atrioventricular canal and for cardiac looping, and that perturbation in Tgfbeta 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.

Topics: Animals; Cell Differentiation; Endocardial Cushion Defects; Fluorescent Antibody Technique; Heart; In Situ Hybridization; Mesoderm; Mice; Mice, Mutant Strains; Microdissection; Models, Animal; Signal Transduction; Transforming Growth Factor beta