Loss of 2-spectrin prevents cardiomyocyte differentiation and heart development

2-Spectrin is an actin-binding protein that plays an important role in membrane integrity and the transforming growth factor (TGF)- signalling pathway as an adaptor for Smads. Loss of 2-spectrin in mice (Spnb2(/)) results in embryonic lethality with gastrointestinal, liver, neural, and heart abnormalities that are similar to those in Smad2(/)Smad3(/) mice. However, to date, the role of 2-spectrin in embryogenesis, particularly in heart development, has been poorly delineated. Here, we demonstrated that 2-spectrin is required for the survival and differentiation of cardiomyocytes, and its loss resulted in defects in heart development with failure of ventricular wall thickening. Disruption of 2-spectrin in primary muscle cells not only inhibited TGF-/Smad signalling, but also reduced the expression of the cardiomyocyte differentiation markers Nkx2.5, dystrophin, and -smooth muscle actin (-SMA). Furthermore, cytoskeletal networks of dystrophin, F-actin, and -SMA in cardiomyocytes were disorganized upon loss of 2-spectrin. In addition, deletion of 2-spectrin in mice (Spnb2(tm1a/tm1a)) prevented proper development of the heart in association with disintegration of dystrophin structure and markedly reduced survival. These data suggest that 2-spectrin deficiency leads to inactivation of TGF-/Smad signalling and contributes to dysregulation of the cell cycle, proliferation, differentiation, and the cytoskeletal network, and it leads to defective heart development. Our data demonstrate that 2-spectrin is required for proper development of the heart and that disruption of 2-spectrin is a potential underlying cause of congenital heart defects.