Abstract
Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3−/− fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3−/− fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3−/− fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFβ3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFβ3 was required for collagen matrix reorganization. Biochemical studies indicated the ‘paradoxically’ increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFβ3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFβ signaling pathways.
Highlights
Transforming growth factor beta3 (TGFβ3) is a multifunctional growth factor and cytokine well-known for its involvement in craniofacial development [1,2,3,4,5]
Impaired myocardium of the interventricular septum was associated with the muscular type of the ventricular septal defect (VSD) in the Tgfb3−/− fetuses (Figure 1A,C and Figure S1D,E)
In situ hybridization analysis of wildtype hearts (E12.5) detected higher expression of Tgfb3 in the compact and trabecular myocardium of the right ventricle and to a lesser degree in the left ventricle (Figure 1D,E). These results indicate that TGFβ3 is required for ventricular myocardial development and that it plays a more important role in the formation of the right ventricle
Summary
Transforming growth factor beta (TGFβ3) is a multifunctional growth factor and cytokine well-known for its involvement in craniofacial development [1,2,3,4,5]. TGFB3 mutations in Loeys-Dietz Syndrome 5 (LDS5)/Rienhoff syndrome (RNHF) (OMIM#615582) are associated with connective tissue disorders and Marfan syndrome (MFS)-like features, including congenital heart defects (CHD), aortic aneurysms, and valvular disease [9,10,11]. Aorta from LDS5 patients exhibit paradoxically increased TGFβ signaling, which is thought to be involved in the diverse aortopathies [9]. Other features of these patients overlap clinically with Shprintzen–Goldberg syndrome (SGS) (OMIM#182212) and Marfan syndrome (MFS) (OMIM#154700), including cleft palate. De novo TGFB3 mutations cause congenital syndromes characterized by a combination of clinical features of Beals-Hecht syndrome (CCA) (OMIM#121050), RNHF, MFS, and Loeys-Dietz syndrome (LDS) [12,13,14]
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