TGFβ signaling and congenital heart disease: Insights from mouse studies

Abstract

Transforming growth factor β (TGFβ) regulates one of the major signaling pathways that control tissue morphogenesis. In vitro experiments using heart explants indicated the importance of this signaling pathway for the generation of cushion mesenchymal cells, which ultimately contribute to the valves and septa of the mature heart. Recent advances in mouse genetics have enabled in vivo investigation into the roles of individual ligands, receptors, and coreceptors of this pathway, including investigation of the tissue specificity of these roles in heart development. This work has revealed that (1) cushion mesenchyme can form in the absence of TGFβ signaling, although mesenchymal cell numbers may be misregulated; (2) TGFβ signaling is essential for correct remodeling of the cushions, particularly those of the outflow tract; (3) TGFβ signaling also has a role in ensuring accurate remodeling of the pharyngeal arch arteries to form the mature aortic arch; and (4) mesenchymal cells derived from the epicardium require TGFβ signaling to promote their differentiation to vascular smooth muscle cells to support the coronary arteries. In addition, a mouse genetics approach has also been used to investigate the disease pathogenesis of Loeys-Dietz syndrome, a familial autosomal dominant human disorder characterized by a dilated aortic root, and associated with mutations in the two TGFβ signaling receptor genes, TGFBR1 and TGFBR2. Further important insights are likely as this exciting work progresses.

Cilia and coordination of signaling networks during heart development

“…92 Consequently, deregulation of TGFβ/BMP activity almost invariably leads to pathologies in the adult as well as severe developmental defects, including malformation of the OFT, AVC and septa. 19,167 Interestingly, defects in these areas are also found in cilia-related mutants. Further, genomic deletion and duplication of the human gene encoding TGFβ Receptor II, TGFBR2, causes heterotaxy, 17 whereas endothelial cells derived from Ift88/Tg737 −/− mouse embryos show defective TGFβ signaling upon sheer induced EndoMT.…”

Transforming growth factor-β and smooth muscle differentiation

“…Endoglin has been identified as a part of the TGF-β receptor complexes and can be co-precipitated with TβRⅡ and TβRI in endothelial and leukemic cells [72][73][74] . Endoglin has a pivotal function in the development of the cardiovascular system and in vascular remodeling.…”

Analysis of the Role of Crim1 in Heart Development

“…EMT, as previously mentioned, as well as coronary vessel and cushion development (Arthur and Bamforth, 2011). Formation of the cardiac cushions requires endothelial to mesenchymal stimulation in the endocardium, which follows the activation of the TGFβ signalling pathway by different TGFβ isoforms (Boyer et al, 1999).…”

“…TGFβs 1, 2 and 3 are expressed in various stages of heart development and in different locations including endocardial-endothelial cells, the epicardium, the AV canal myocardium and the OFT (Arthur and Bamforth, 2011). The TGFβ receptors and co-receptors are expressed in overlapping sites, and the interaction between ligand and receptors is vital for different aspects of cardiogenesis;…”

“…TGFβ signal transduction is also involved in the differentiation of vascular smooth muscle cells, generated upon the formation of EPDCs after epicardial EMT (Sridurongrit et al, 2008). PDGFR-β is one of the genes upregulated by TGFβ (Xie et al, 2004), and both are involved in EMT and vascular smooth muscle cell development in the heart (Arthur and Bamforth, 2011, Sridurongrit et al, 2008. Further studies will be required to correlate the time of expression of both factors as well as whether they work in synergy to mediate the aforementioned roles.…”